Methods Of Treating Multiple Sclerosis

ABSTRACT

The disclosure relates to methods of treating multiple sclerosis. Also provided are pharmaceutical products containing ponesimod, instructions for use of ponesimod, methods for selling a drug product containing ponesimod, and methods for reducing clinical management events before or during treatment of multiple sclerosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 63/254,369, filed Oct. 11, 2021, the disclosure of whichis incorporated by reference herein.

TECHNICAL FIELD

The present disclosure relates to methods of treating multiplesclerosis.

BACKGROUND

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease ofthe central nervous system affecting approximately 2.5 million peopleworldwide. The disease is clinically perceived by relapses andprogressive loss of neurological function, primarily attributed todemyelination, axonal loss, and gliosis culminating in long-termmultifocal sclerotic plaques in the brain and spinal cord leading toneurological impairment and severe disability. The two main subtypes ofMS are relapsing forms of MS (RMS) which represent 85% of MS patientsand include relapsing-remitting disease (RRMS), clinically isolatedsyndrome, and active secondary progressive disease; and primaryprogressive MS (PPMS) which affects only 15% of MS patients.

Relapses are defined as newly appearing neurological symptoms in theabsence of fever or infections that last for more than 24 hours.Relapses may fully recover over days or weeks or lead to persistentresidual deficits and accumulation of disability.

The natural history of MS is usually divided into two partiallyoverlapping phases, a predominantly inflammatory phase and apredominantly degenerative phase: after an initial phase of relapsingremitting MS, driven by inflammatory mechanism, patients experience asecondary progressive MS characterized by continuous worsening ofsymptoms independent of the occurrence of relapses, the degenerativephase of MS. Most currently available disease-modifying treatments(DMTs) address the inflammatory phase of MS and are less efficacious inthe degenerative phase.

Current medical practice encourages early intervention withdisease-modifying treatments, with the intent of optimizing long-termclinical outcomes.

Key objectives in the management of MS are reducing the rate of relapsesand preventing or at least delaying disease progression. Most of thedisease-modifying drugs approved for MS have to be administered byinjection or infusion (subcutaneous [s.c.], intramuscular [i.m.], orintravenous [i.v.] route). Recently, new disease-modifying drugsadministered orally have been approved for RMS.

The following injectable drugs have been approved in at least onecountry for the treatment of MS:

-   -   Interferon (IFN) β-1a 30 mcg i.m. once weekly (Avonex®)    -   IFN β-1a 22 or 44 mcg s.c. 3 times weekly (Rebif®)    -   IFN β-1b 250 mcg s.c. every other day (Betaferon®, Extavia®)    -   Pegylated IFN β-1a 125 mcg subcutaneously every 2 weeks        (Plegridy®)    -   Glatiramer acetate 20 mg s.c. once a day (o.d.) or 40 mg        subcutaneously 3 times weekly (Copaxone®)    -   Glatiramer acetate 20 mg s.c. o.d. (Glatopa®)    -   Natalizumab 300 mg i.v. every 4 weeks (Tysabri®)    -   Mitoxantrone i.v. every 3 months (Novantrone®)    -   Alemtuzumab concentrate for solution for infusion, 12 mg        alemtuzumab in 1.2 mL (10 mg/mL) (Lemtrada®)

Several oral drugs have also been approved for MS:

-   -   Fingolimod 0.5 mg orally o.d. (Gilenya®)    -   Teriflunomide 7 mg, 14 mg o.d. (Aubagio®)    -   Dimethyl fumarate (BG-12) gastro-resistant hard capsules 120/240        mg twice daily (Tecfidera®)    -   Cladribine 40 to 100 mg orally per treatment week (Mavenclad®)

Sphingosine-1-phosphate (SIP) plays a central role in lymphocytetrafficking. SIP is synthesized and secreted by many cell types,including platelets, erythrocytes, and mast cells, and elicits a varietyof physiological responses. Lymphocyte egress from primary and secondarylymphoid organs is dependent on the SiP1 receptor. SiP1 receptormodulators block lymphocyte migration out of lymphoid tissue into thelymphatic and vascular circulation, thereby reducing peripherallymphocyte counts and preventing lymphocyte recruitment to sites ofinflammation. Following withdrawal of an SiP1 receptor agonist, thefunctional lymphocytes return to the circulation from their sites ofsequestration. Other functions that do not rely on homing mechanisms,such as antibody generation by B lymphocytes, first-line immunologicalprotection by granulocytes and monocytes, and antigen-dependent T-cellactivation and expansion, are not affected by this mechanism.

S1P itself induces pleiotropic effects, which are mediated by a familyof five G protein-coupled receptors, SiP1-SiP5, located on endothelialcells, vascular and cardiac smooth muscle cells, and cardiac myocytes.The first S1P receptor modulator, fingolimod (FTY720, Gilenya®), whichhas been approved by the FDA and the EMA for the treatment of MS, is notselective for the S1P1 receptor but interacts with S1P3, S1P4, and S1P5.

Ponesimod, an iminothiazolidinone derivative, is an orally active,selective modulator of the S1P1 that induces a rapid, dose-dependent,and reversible reduction in peripheral blood lymphocyte count byblocking the egress of lymphocytes from lymphoid organs. T and B cellsare most sensitive to ponesimod mediated sequestration. In contrast,monocyte, natural killer (NK) cell and neutrophil counts are not reducedby ponesimod. Ponesimod is commercially available as PONVORY™, aonce-daily oral medication. In the United States the Food and DrugAdministration (FDA) has approved PONVORY™ to treat adults withrelapsing forms of multiple sclerosis (MS), to include clinicallyisolated syndrome, relapsing-remitting disease, and active secondaryprogressive disease.

In the pharmaceutical industry, the path from drug discovery to reachingan approved product is riddled with uncertainty. That path is one thatsince 2010 and out of more than 12,000 clinical studies, there is verylow likelihood of regulatory approval of less than 10% (from Phase 1 toapproval). The final path to approval is also not a certainty norinevitable as failures continue as late as from Phase 3 to approval.This is not only due to the high unpredictability and uncertaintyregarding how a pharmaceutical product will impact human biology, butoften human behavior is unpredictable in how data is interpreted byregulatory agencies and whether the data warrants approving a study drugas an approved product for use in commerce.

SUMMARY

The disclosure relates to a pharmaceutical product comprising ponesimod,wherein the pharmaceutical product is packaged, and wherein the packageincludes a label that identifies ponesimod as an approved product forthe treatment of multiple sclerosis. In some embodiments, the patient'smultiple sclerosis is relapsing multiple sclerosis. In otherembodiments, the relapsing multiple sclerosis comprisesrelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.

The disclosure provides methods for treating multiple sclerosis in apatient in need thereof, comprising administering an approved productcomprising ponesimod in an amount and manner that is described in a drugproduct label for the approved product and/or in a treatment regimendescribed herein.

The disclosure also provides methods of selling an approved productcomprising ponesimod, said method comprising selling such drug product,wherein a drug product label for a reference listed drug for such drugproduct includes instructions for treating a patient with multiplesclerosis.

The disclosure further provides methods of offering for sale a drugproduct comprising ponesimod, said method comprising offering for salesuch drug product, wherein a drug product label for a reference listeddrug for such drug product includes instructions for treating a patientwith multiple sclerosis.

The disclosure further provides methods for reducing clinical managementevents and/or for easing use of drug treatment for treating multiplesclerosis in a patient in need thereof, comprising administeringponesimod in an amount and manner that is described in a drug productlabel for an approved product and/or in a treatment regimen describedherein, namely administration of about 20 mg of ponesimod orally oncedaily, with or without utilization of the up-titration dosing procedurealso described herein.

The disclosure is also directed to an approved drug product as definedherein, wherein the pharmaceutical product comprises ponesimod in tabletform.

The disclosure also provides methods for concomitant treatment of abeta-blocker and ponesimod in a patient in need thereof, wherein thepatient is being treated with the beta-blocker and ponesimod treatmentis to be initiated, and wherein the patient has a resting heart rate ofgreater than 55 beats per minute during treatment with the beta-blockand prior to initiation of ponesimod, comprising administering ponesimodwithout interruption to the beta-blocker treatment.

In other embodiments, the disclosure is directed to methods forconcomitant treatment of a beta-blocker and ponesimod for a patient inneed thereof, wherein the patient is being treated with the beta-blockerand ponesimod treatment is to be initiated, and wherein the patient hasa resting heart rate of less than or equal to 55 beats per minute duringtreatment with the beta-block and prior to initiation of ponesimod,comprising interrupting the beta-blocker treatment until the patient'sheart rate is greater than 55 beats per minute and initiating ponesimodtreatment in a titration regimen comprising administering orally oncedaily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mgof ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod onday 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimod on days 12,13, and 14, followed by administering a 20 mg maintenance dose ofponesimod once daily thereafter, and reinitiating the beta-blocker afterponesimod has been up-titrated to the maintenance dosage.

The disclosure also relates to methods of treating multiple sclerosis ina patient in need thereof, wherein the patient has sinus bradycardia,first or second degree AV block, or a history of myocardial infarctionor heart failure occurring more than 6 months prior to the initiation ofponesimod treatment, comprising administering an effective regimen ofponesimod to the patient, wherein after a first dose of the ponesimod,the patient is monitored for a period of 4 hours for symptoms ofbradycardia. In other embodiments, no first dose monitoring is neededwherein the patient has no sinus bradycardia, no first or second degreeAV block, and no history of myocardial infarction or heart failureoccurring more than 6 months prior to the initiation of ponesimodtreatment.

The disclosure further provides methods of reinitiating treatment withponesimod following a missed dose in a patient in need thereof, whereinthe patient is being treated with an oral, once daily 20 mg maintenancedose and fewer than four consecutive maintenance doses have been missed,comprising resuming treatment with the maintenance dose.

In other embodiments, the disclosure is directed to methods ofreinitiating ponesimod following a missed dose for a patient in needthereof, wherein the patient is being treated with an oral, once daily20 mg maintenance dose or a 14-day titration regimen comprisingadministering orally once daily titration doses of 2 mg of ponesimod ondays 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod ondays 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimodon day 11; and 10 mg of ponesimod on days 12, 13, and 14, and four ormore consecutive maintenance doses or titration doses have been missed,comprising reinitiating ponesimod with the 14-day titration regimen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the testing strategy for the study described in Example 1.

FIG. 2A shows an overview of primary and main supplementary analyses ofrelapses (Forest plot with 99% CL). In FIG. 2A, n(Pon)=No. of subjectsin ponesimod arm; rate(Pon)=mean rate in ponesimod arm; n(Ter)=No. ofsubjects in teriflunomide arm; and rate(Ter)=mean rate in teriflunomidearm. *=Conducted on the Per Protocol Set; **=Relapses with missing EDSSare imputed as confirmed relapses. FIG. 2B shows the conceptualframework for the Fatigue Symptoms and Impact Questionnaire−RelapsedMultiple Sclerosis (FSIQ-RMS); *=items also present in physical impactssubdomain.

FIG. 3A shows change from baseline up to week 108 for the FSIQ-RMSweekly symptoms score by visit. MMRM (Main analysis) Analysis Set: FullAnalysis Set. In FIG. 3A, subjects with available baseline and at leastone post-baseline result are included in the analysis, wherebyMMRM=mixed effects repeated measurements model with unstructuredcovariance, treatment, visit, treatment by visit interaction, baselineby visit interaction as fixed effects, baseline FSIQ score, EDSS strata(<=3.5, >3.5), DMT in last 2 years prior randomization strata (Y,N) ascovariates.

FIG. 3B shows cumulative distribution function of change from baselineat week 108 for the FSIQ-RMS weekly symptoms score.

FIG. 4 is a Kaplan-Meier curve (main analysis) showing the time to first12-week confirmed disability accumulation (CDA) up to end-of-study(EOS): Analysis Set: Full Analysis Set. In FIG. 4 , an event=12 week CDAand subjects without event are censored at their last EDSS assessmentwithout EDSS increase. Unstratified Kaplan-Meier estimates arepresented. Bars on graph display pointwise 95% confidence intervals ofthe estimate. P-value is two-sided and based on the stratified log-ranktest. Hazard ratio estimate obtained from stratified Cox regression withWald confidence limits. Analysis is stratified by EDSS strata(<3.5; >3.5) and disease modifying therapy in last 2 years prior torandomization strata (Y,N).

FIG. 5 is a Kaplan-Meier curve (Main analysis) showing the time to first24-week CDA up to EOS: Analysis Set: Full Analysis Set. In FIG. 5 , anevent=24 week CDA and subjects without event are censored at their lastEDSS assessment without EDSS increase. Unstratified Kaplan-Meierestimates are presented. Bars on graph display pointwise 95% confidenceintervals of the estimate. P-value is two-sided and based on thestratified log-rank test. Hazard ratio estimate obtained from stratifiedCox regression with Wald confidence limits. Analysis is stratified byEDSS strata (<3.5; >3.5) and disease modifying therapy in last 2 yearsprior to randomization strata (Y,N).

FIG. 6 shows the 12-lead electrocardiogram (ECG) heart rate and absolutechange from pre-dose at Day 1, by hour (Analysis Set: Safety Set). Asper up-titration regimen, the dose of ponesimod on Day 1 is 2 mg.

FIG. 7 is a Forest plot (with 99% CL) showing an overview of primary andsensitivity analyses for confirmed relapses up to EOS (Analysis Set:Full Analysis Set). In FIG. 7 , n(Pon)=subjects in ponesimod group;rate(Pon)=annualized relapse rate in ponesimod group; n(Ter)=subjects interiflunomide group and rate(Ter)=annualized relapse rate interiflunomide group. The vertical solid line references the treatmenteffect from the main analysis. Negative binomial model is applied withWald confidence limits, offset: log time (years) up to EOS. The mainanalysis is adjusted for the following covariates: EDSS strata(<3.5; >3.5); DMT in last 2 years prior to randomization strata (Y,N);and number of relapses in year prior to study entry (<1; >2).

FIG. 8 is a Forest plot (with 99% CL) showing subgroup analyses ofconfirmed relapses up to EOS (Analysis Set: Full Analysis Set). In FIG.8 , p*=interaction p-value; n(Pon)=no. of subjects in ponesimod group;rate(Pon)=mean rate in ponesimod group; n(Ter)=no. of subjects interiflunomide group and rate(Ter)=mean rate in teriflunomide group.Negative binomial model is applied with Wald confidence limits, offset:log time (years) up to EOS, in each subgroup separately. Interactionp-value is from likelihood ratio test of interaction term in model withtreatment, subgroup and treatment by subgroup interactions. The verticalsolid line references the treatment effect from the main analysis. Themain analysis is adjusted for the following covariates: EDSS strata(<3.5; >3.5); DMT in last 2 years prior to randomization strata (Y,N);and number of relapses in year prior to study entry (<1; >2). Analysesin subgroups are not adjusted for covariates.

FIG. 9 shows change from baseline to week 108 in the FSIQ-RMS for thephysical impact sub-domain.

FIG. 10 shows change from baseline to week 108 in the FSIQ-RMS for thecognitive/emotional impacts sub-domain.

FIG. 11 shows change from baseline to week 108 in the FSIQ-RMS for thecoping impact sub-domain.

FIG. 12 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients with baseline fatigue below the median.

FIG. 13 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients with baselinefatigue below the median.

FIG. 14 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients with baseline fatigue above the median.

FIG. 15 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients with baselinefatigue above the median.

FIG. 16 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients without DMT treatment two years prior torandomization.

FIG. 17 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients without DMTtreatment two years prior to randomization.

FIG. 18 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients without Gd+/T1 lesions at baseline.

FIG. 19 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients withoutGd+/T1 lesions at baseline.

FIG. 20 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients with Gd+/T1 lesions at baseline.

FIG. 21 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients with Gd+/T1lesions at baseline.

FIG. 22 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients with baseline EDSS ≤3.5.

FIG. 23 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients with baselineEDSS ≤3.5.

FIG. 24 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients having one or fewer relapses at baseline.

FIG. 25 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients having one orfewer relapses at baseline.

FIG. 26 shows change from baseline to week 108 in FSIQ-RMS weeklysymptoms score for patients having two or more relapses at baseline.

FIG. 27 shows cumulative distribution function of change from baselineat week 108 in FSIQ-RMS weekly symptoms score for patients having two ormore relapses at baseline.

FIG. 28 depicts a bar graph of the total number of differential eventsin each of the administrative claims databases for each S1P.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In the present disclosure the singular forms “a”, “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “amaterial” is a reference to at least one of such materials andequivalents thereof known to those skilled in the art, and so forth.

When a value is expressed as an approximation by use of the descriptor“about” or “substantially” it will be understood that the particularvalue forms another embodiment. In general, use of the term “about” or“substantially” indicates approximations that can vary depending on thedesired properties sought to be obtained by the disclosed subject matterand is to be interpreted in the specific context in which it is used,based on its function. The person skilled in the art will be able tointerpret this as a matter of routine. In some cases, the number ofsignificant figures used for a particular value may be one non-limitingmethod of determining the extent of the word “about” or “substantially”.In other cases, the gradations used in a series of values may be used todetermine the intended range available to the term “about” or“substantially” for each value. Where present, all ranges are inclusiveand combinable. That is, references to values stated in ranges includeevery value within that range.

When a list is presented, unless stated otherwise, it is to beunderstood that each individual element of that list and everycombination of that list is to be interpreted as a separate embodiment.For example, a list of embodiments presented as “A, B, or C” is to beinterpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A orC,” “B or C,” or “A, B, or C.”

It is to be appreciated that certain features of the disclosure whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.That is, unless obviously incompatible or excluded, each individualembodiment is deemed to be combinable with any other embodiments andsuch a combination is considered to be another embodiment. Conversely,various features of the disclosure that are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any sub-combination. It is further noted that the claims may bedrafted to exclude any optional element. As such, this statement isintended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.Finally, while an embodiment may be described as part of a series ofsteps or part of a more general structure, each said step may also beconsidered an independent embodiment in itself.

In some aspects, the present disclosure is directed to methods ofavoiding worsening of fatigue-related symptoms in a human patientsuffering from multiple sclerosis and fatigue, comprising, optionally,assessing the fatigue-related symptoms of the patient; and administeringan effective regimen of ponesimod to the patient, wherein the regimen issufficient to avoid worsening of the fatigue-related symptoms. Asdescribed herein, fatigue is fatigue associated with multiple sclerosis.

In certain aspects, the methods are directed to patients that have hadno prior disease modifying treatment (DMT) for multiple sclerosis withinabout two years prior to initiation of treatment with ponesimod. In someembodiments, the methods are directed to patients that have a baselineexpanded disability status scale (EDSS) score of <3.5 prior toinitiation of treatment with ponesimod. In other embodiments, themethods are directed to patients that have no Gd+/T1 lesions prior toinitiation of treatment with ponesimod. Baseline refers to a time periodprior to initiation of treatment with ponesimod and/or standard of caretreatment. This time period is typically up to about 45 days prior toinitiation of treatment, including, for example, up to about 40 days, upto about 35 days, up to about 30 days, up to about 25 days, up to about20 days, up to about 15 days, or up to about 10 days prior to initiationof treatment with ponesimod and/or standard of care treatment.

In other aspects, the present disclosure is directed to methods ofreducing the number of combined unique active lesions (CUALs) in apatient suffering from multiple sclerosis, comprising administering aneffective regimen of ponesimod to the patient, wherein the regimen issufficient to reduce the number of CUALs by at least 40% relative to apatient population at substantially the same level of diseaseprogression receiving a standard of care treatment that does notcomprise ponesimod.

In some aspects, the methods of the disclosure are performed on a humanpatient suffering from multiple sclerosis. In some embodiments, thepatient's multiple sclerosis is relapsing multiple sclerosis. In otherembodiments, the relapsing multiple sclerosis comprisesrelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.

As used herein, the term “avoiding worsening of fatigue-relatedsymptoms” refers to preventing the patient's fatigue-related symptomsfrom becoming worse relative to the patient's fatigue-related symptomsat baseline, wherein baseline refers to a time period prior toinitiation of treatment with ponesimod. This time period is typically upto about 45 days prior to initiation of treatment with ponesimod,including, for example, up to about 40 days, up to about 35 days, up toabout 30 days, up to about 25 days, up to about 20 days, up to about 15days, or up to about 10 days prior to initiation of treatment withponesimod. By avoiding worsening, the methods otherwise relate tostabilizing or improving fatigue-related symptoms.

In some embodiments of the methods of the disclosure, the patient'sfatigue-related symptoms are assessed. In some embodiments of themethods of the disclosure, the patient's fatigue-related symptoms arenot assessed prior to initiation of treatment with ponesimod. As usedherein, “fatigue-related symptoms” refer to symptoms of fatigueexperienced by the patient.

In some aspects, the fatigue-related symptoms are symptoms experiencedby the patient while doing routine daily activities (e.g. housework,yard work, shopping, working). In some embodiments, the fatigue-relatedsymptoms are those experienced by the patient while doing routine dailyactivities and include being physically tired, being mentally tired,being physically weak, lacking energy, feeling worn out, or feelingsleepy.

In other embodiments, the fatigue-related symptoms are (1) beingphysically tired, (2) being mentally tired, (3) being physically weak,(4) lacking energy, (5) feeling worn out, (6) feeling sleepy while doingroutine daily activities, and (7) feeling worn out while at rest.

In some embodiments, the patient's fatigue-related symptoms are assessedbefore initiation of ponesimod administration, for example, at baseline.In other embodiments, the patient's fatigue-related symptoms areassessed after initiation of ponesimod administration to, for examplemonitor the fatigue-related symptoms during the treatment withponesimod. In some embodiments, the patient's fatigue-related symptomsare assessed both before initiation of ponesimod administration andafter initiation of ponesimod therapy.

The patient's fatigue-related symptoms may be assessed by ascertainingfrom the patient the nature and severity of any symptoms of fatigueexperienced by the patient. In some embodiments, the patient'sfatigue-related symptoms are assessed using a patient-reported outcome(PRO) questionnaire.

In some embodiments, the patient-reported outcome questionnaire is theFatigue Symptoms and Impact Questionnaire—Relapsing Multiple Sclerosis(FSIQ-RMS) (available from Mapi Research Trust). The FSIQ-RMS is an MSspecific 20-item PRO measure that comprises 2 domains: one measuring MSsymptoms and one measuring MS-related impacts. See Hudgens S, et al.,Development and Validation of the FSIQ-RMS: A New Patient-ReportedQuestionnaire to Assess Symptoms and Impacts of Fatigue in RelapsingMultiple Sclerosis. Value Health. 2019 April; 22(4):453-466. doi:10.1016/j.jval.2018.11.007. Epub 2019 Feb. 21. PubMed PMID: 30975397.With 7 symptom items and 13 impact items (in 3 impacts subdomains:physical, cognitive and emotional, and coping), the FSIQ-RMS is acomprehensive, valid, and reliable measure of fatigue-related symptomsand impacts in RMS patients. FIG. 2B depicts a conceptual framework forthe FSIQ-RMS.

In some embodiments, the patient-reported outcome questionnaire is thesymptom domain of the FSIQ-RMS. The FSIQ-RMS symptom domain (FSIQ-RMS-S)consists of seven items assessing fatigue-related symptoms with a recallperiod of 24 hours measured on an 11-point numeric rating scale; thestandardized symptom domain score ranges from 0 to 100 with a higherscore indicating greater fatigue. This domain (i.e., section 1 of thequestionnaire) is completed on 7 consecutive days.

The FSIQ-RMS impact domain (FSIQ-RMS-I) consists of 13 items assessingimpacts of fatigue-related symptoms with a recall period of 7 daysmeasured on a 5-point verbal descriptor scale, the standardized impactdomain score ranges from 0 to 100 with a higher score indicating greaterimpact.

In some aspects of the methods of the present disclosure, the patient isadministered an effective regimen of ponesimod. An effective regimen isone that elicits the biological or medicinal response in a human tissuesystem that is being sought by a researcher, medical doctor, or otherclinician, which includes alleviation of one or more symptoms of thedisease or disorder being treated.

As used herein, the term “ponesimod” refers to the compound(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one,which has the following structure:

In some embodiments, “ponesimod” also refers to pharmaceuticallyacceptable salts of ponesimod. The term “pharmaceutically acceptablesalt” refers to salts that retain the desired biological activity of thesubject compound and exhibit minimal undesired toxicological effects.Such salts include inorganic or organic acid and/or base addition saltsdepending on the presence of basic and/or acidic groups in the subjectcompound. For reference see for example Handbook of PharmaceuticalSalts. Properties, Selection and Use, P. Heinrich Stahl, Camille G.Wermuth (Eds.), Wiley-VCH, 2008 and Pharmaceutical Salts andCo-crystals, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012.

It is to be understood that the present disclosure encompasses ponesimodin any form including amorphous as well as crystalline forms. It isfurther to be understood that crystalline forms of ponesimod encompassesall types of crystalline forms including polymorphs, solvates andhydrates, salts and co-crystals (when the same molecule can beco-crystallized with different co-crystal formers) provided they aresuitable for pharmaceutical administration. In some embodiments,ponesimod is in crystalline form A or crystalline form C as described inWO 2010/046835, incorporated herein by reference. In some embodiments,ponesimod is in crystalline form C.

It should be noted that the amounts of ponesimod described herein areset forth on a ponesimod free base basis. That is, the amounts indicatethat amount of the ponesimod molecule administered, exclusive of, forexample, solvent (such as in solvates) or counterions (such as inpharmaceutically acceptable salts).

In some embodiments, the effective regimen comprises a daily dose ofponesimod. In some embodiments, the daily dose of ponesimod isadministered orally.

In some embodiments, the daily dose of ponesimod is administered oncedaily.

In some embodiments, the daily dose of ponesimod is about 15 to about 25mg. In further embodiments, the daily dose of ponesimod is about 15 mg,about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg. In certainembodiments, the daily dose of ponesimod is about 20 mg.

In some embodiments, about 20 mg of ponesimod is administered orallyonce daily.

In other embodiments, the effective regimen comprises an up-titration,followed by a daily maintenance dose of ponesimod. An up-titration is adosing procedure in which the daily dose of ponesimod is graduallyincreased over a period of days, culminating with administration of themaintenance dose.

In some embodiments, the regimen comprises an up-titration at theinitiation of the method of the disclosure. In other embodiments, theregimen comprises an up-titration upon re-initiation of the method aftera discontinuation of the method of the disclosure. As used herein, “uponre-initiation of the method after a discontinuation” means aninterruption of the administration of ponesimod of at least one, atleast two or preferably at least 3 days before treatment isre-initiated. In some embodiments, the regimen comprises an up-titrationstep at initiation of the method or upon re-initiation of the methodafter a discontinuation.

In some embodiments of the methods of the disclosure, the up-titrationregimen one disclosed in U.S. Pat. No. 10,220,023, incorporated hereinby reference. For example, in certain aspects, the up-titrationcomprises administering orally once daily about 2 mg of ponesimod ondays 1 and 2; about 3 mg of ponesimod on days 3 and 4; about 4 mg ofponesimod on days 5 and 6; about 5 mg of ponesimod on day 7; about 6 mgof ponesimod on day 8; about 7 mg of ponesimod on day 9; about 8 mg ofponesimod on day 10; about 9 mg of ponesimod on day 11; and about 10 mgof ponesimod on days 12, 13, and 14.

In other embodiments of the methods of the disclosure, the up-titrationcomprises administering orally once daily 2 mg of ponesimod on days 1and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg ofponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod onday 11; and 10 mg of ponesimod on days 12, 13, and 14.

In some embodiments, the maintenance dose is about 20 mg of ponesimodonce daily.

In some embodiments, the regimen comprises an up-titration step atinitiation of the method or upon re-initiation of the method after adiscontinuation, comprising administering orally once daily 2 mg ofponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg ofponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimodon day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; and 9mg of ponesimod on day 11; 10 mg of ponesimod on days 12, 13, and 14,followed by the administering of the 20 mg of ponesimod once dailythereafter.

In some aspects of the disclosed methods, the regimen is sufficient toavoid worsening of the fatigue-related symptoms. A regimen is sufficientto avoid worsening of the fatigue-related symptoms when the patient'sfatigue-related symptoms (assessed as described herein) afteradministration of the ponesimod regimen, are either improved orunchanged compared to the patient's fatigue-related symptoms (assessedas described herein) prior to administration of the ponesimod regimen,for example, at baseline.

In other embodiments, the methods of the disclosure are directed toreducing the number of combined unique active lesions (CUALs) in apatient.

CUALs are new Gd+T1 lesions plus new or enlarging T2 lesions (withoutdouble-counting of lesions). The cumulative number of CUAL is considereda reliable outcome measure of inflammatory MS disease activity.Radiological evidence of disease activity is routinely used to supportdisease diagnosis and to inform therapeutic decisions targeting noevidence of disease activity (NEDA), clinical (relapses or disabilityaccumulation) or radiological (brain lesions on MRI) perspective. SeeLublin F D. Disease activity free status in MS. Mult Scler Relat Disord.2012 January; 1(1):6-7. doi: 10.1016/j.msard.2011.08.001. Epub 2011 Aug.27. PubMed PMID: 25876444.

CUALs are detected using magnetic resonance imaging (MRI) techniques.

In this aspect of the disclosed methods, the ponesimod regimenadministered to the patient is sufficient to reduce the number of CUALsby at least 40% relative to a patient population at substantially thesame level of disease progression receiving a standard of caretreatment. That is, the patient administered the ponesimod regimen willhave acquired at least 40% fewer CUALs as compared to a patient havingsubstantially the same degree of MS progression who is receiving astandard of care treatment.

In some embodiments, the ponesimod regimen administered to the patientis sufficient to reduce the number of CUALs by at least 20% to about 65%relative to a patient population at substantially the same level ofdisease progression receiving a standard of care treatment. In someembodiments, the ponesimod regimen administered to the patient issufficient to reduce the number of CUALs by at least 30% relative to apatient population at substantially the same level of diseaseprogression receiving a standard of care treatment. In some embodiments,the ponesimod regimen administered to the patient is sufficient toreduce the number of CUALs by at least 50% relative to a patientpopulation at substantially the same level of disease progressionreceiving a standard of care treatment. In some embodiments, theponesimod regimen administered to the patient is sufficient to reducethe number of CUALs by at least 55% relative to a patient population atsubstantially the same level of disease progression receiving a standardof care treatment.

As used herein, the term “standard of care treatment” refers to aphysician-prescribed treatment of MS. In some embodiments, the standardof care comprises, consists of, or consists essentially of administeringan MS treatment that has been approved by a regulatory authority. Insome embodiments, the standard of care treatment is Interferon (IFN)β-1a 30 mcg i.m. once weekly (Avonex®), IFN β-1a 22 or 44 mcg s.c. 3times weekly (Rebif®), IFN β-1b 250 mcg s.c. every other day(Betaferon®, Extavia®), Pegylated IFN β-1a 125 mcg subcutaneously every2 weeks (Plegridy®), Glatiramer acetate 20 mg s.c. once a day (o.d.) or40 mg subcutaneously 3 times weekly (Copaxone®), Glatiramer acetate 20mg s.c. o.d. (Glatopa®), Natalizumab 300 mg i.v. every 4 weeks(Tysabri®), Mitoxantrone i.v. every 3 months (Novantrone®), Alemtuzumabconcentrate for solution for infusion, 12 mg alemtuzumab in 1.2 mL (10mg/mL) (Lemtrada®), Fingolimod 0.5 mg orally o.d. (Gilenya®),Teriflunomide 7 mg, 14 mg o.d. (Aubagio®), Dimethyl fumarate (BG-12)gastro-resistant hard capsules 120/240 mg twice daily (Tecfidera®), orCladribine 40 to 100 mg orally per treatment week (Mavenclad®).

In some embodiments, the standard of care treatment comprises a S1Preceptor modulator that is not ponesimod.

In other embodiments, the standard of care treatment comprisesteriflunomide. In some embodiments, the standard of care treatmentcomprises administration of about 14 mg of teriflunomide orally oncedaily.

In some embodiments, the patient has had no prior disease modifyingtreatment (DMT) for multiple sclerosis. In some embodiments, the patienthas had no prior disease modifying treatment (DMT) for multiplesclerosis within about two years prior to initiation of treatment withponesimod. In some embodiments, patients that have had no prior DMT formultiple sclerosis realize improved efficacy from use of ponesimod toaddress fatigue with respect to a standard of care treatment that doesnot comprise ponesimod, such as teriflunomide. Accordingly, with respectto these patients and others, the disclosed methods provide health careproviders with options for improved outcomes compared to standard ofcare.

In some embodiments, the methods are directed to patients having abaseline expanded disability status scale (EDSS) score of <3.5. In someembodiments, the methods are directed to patients having no Gd+/Tllesions at baseline.

The present disclosure also provides pharmaceutical products comprisingponesimod. Typically, the pharmaceutical product is a package or ispackaged, for example, a bottle, a pouch, or a blister pack.

In some embodiments, the package includes instructions. In certainembodiments, instructions are for administering ponesimod to a humanpatient suffering from multiple sclerosis and fatigue in a regimen thatis effective to avoid worsening of fatigue-related symptoms. In otherembodiments, the package provides instructions and/or fatigue-relatedsymptom data directed to patients having had no prior disease modifyingtreatment (DMT) for multiple sclerosis for a period of about two years.In further embodiments, the package provides instructions and/orfatigue-related symptom data directed to patients having a baselineexpanded disability status scale (EDSS) score of <3.5. In yet otherembodiments, the package provides instructions and/or fatigue-relatedsymptom data directed to patients having no Gd+/T1 lesions at baseline.

As used herein, the term “group level” refers to a group level change ordifference between groups of patients, e.g., group level differences inan outcome seen in clinical trials when comparing the treatment groups.For instance, FIG. 3A shows the mean change from baseline for ponesimod20 mg and teriflunomide 14 mg over time—and it visually shows theseparation or difference in change from baseline in the treatmentgroups.

As used herein, the term “patient level” refers to individual or withinpatient level of change. As used herein, “clinically meaningful” refersto the practical importance of a treatment effect and whether it has areal genuine, palpable, noticeable effect on symptoms and/or daily life.When interpreting data from a Patient Reported Outcome (PRO), forexample, it is helpful to define a level of change on the PRO score overa predetermined time period that should be interpreted as a treatmentbenefit. Various terms are used for this level of change, includingmeaningful change threshold (MCT). Ibis threshold can be used to conducta responder analysis where an individual patient is a responder if thelevel of change on the PRO score for that patient exceeds the MCT. Theproportion of responders between treatment groups can be compared toevaluate treatment effect. For example, in certain embodiments disclosedherein, there is an analysis of the percentage of responders in theponesimod and teriflunomide treatment groups using an MCT of −6.3 on theFSIQ-RMS weekly symptom score. The percentage of subjects in the stableor improved category is also calculated. And the percentage ofresponders can also be visualized on a graph (a cumulative distributionfunction) which shows the cumulative percentage of patients showing allpossible levels of change in the respective treatment groups.Accordingly, evaluation of within patient changes using MCT andassociated responder analyses are used to provide additionalinterpretation to a p-value derived from a statistical test

As used herein, the term “statistically significant” refers to thelikelihood that a relationship between two or more variables is causedby something other than chance. A p-value less than 0.05 (typically<0.05) is a common metric for statistical significance and is indicativeof strong evidence against the null hypothesis, as there is less than a5% probability the null is correct (and the results are random).

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound described herein to prevent the onset ofthe symptoms or complications, alleviate one or more of the symptoms orcomplications, or eliminate the disease, condition, or disorder.

The disclosure further relates to a pharmaceutical product comprisingponesimod, wherein the pharmaceutical product is packaged, and whereinthe package includes a label that identifies ponesimod as a an approvedproduct for the treatment of multiple sclerosis. In some embodiments,the patient's multiple sclerosis is relapsing multiple sclerosis. Inother embodiments, the relapsing multiple sclerosis comprisesrelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.

The disclosure provides methods for treating multiple sclerosis in apatient in need thereof, comprising administering an approved productcomprising ponesimod in an amount and manner that is described in a drugproduct label for the approved product and/or in a treatment regimendescribed herein.

In certain aspects, methods of selling a drug product comprisingponesimod are also provided. The terms “sale” or “selling” as usedherein refers to transferring a drug product, e.g., a pharmaceuticalcomposition or a dosage form, from a seller to a buyer. In someembodiments, a drug product label for a reference listed drug for thedrug product includes instructions for the treatment of multiplesclerosis.

The term “offering for sale,” as used herein, refers to the proposal ofa sale by a seller to a buyer for a drug product, e.g., a pharmaceuticalcomposition or a dosage form. These methods comprise offering the drugproduct for sale.

The term “drug product” is product that contains an activepharmaceutical ingredient that has been approved for marketing by agovernmental authority, e.g., the Food and Drug Administration or thesimilar authority in other countries. In the context of the presentdisclosure, and as reflected in Example 4, an “approved drug product” asused herein means: a pharmaceutical product that i) has been approvedfor introduction into commerce by a regulatory agency for use intreating adult humans with relapsing forms of multiple sclerosis, toinclude clinically isolated syndrome, relapsing-remitting disease, andactive secondary progressive disease; ii) has an oral, once dailymaintenance dosage of 20 mg of ponesimod and, optionally, a 14-day dosetitration prior to the maintenance dosage of 20 mg, comprisingadministering orally, once daily 2 mg of ponesimod on days 1 and 2; 3 mgof ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg ofponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; 10 mg ofponesimod on days 12, 13, and 14, followed by the 20 mg maintenancedosage of ponesimod on Day 15 and thereafter; and (iii) demonstrated astatistically significant lower annualized relapse rate (ARR), and,optionally, a statistically significant lower number of Gd-enhancing T1lesions and/or a statistically significant lower number of new orenlarging T2 lesions, without double counting of lesions, in a patientpopulation with relapsing forms of MS, wherein the patients had anexpanded disability status scale (EDSS) score of 0 to 5.5 at baseline,had experienced at least one relapse within the year prior, or tworelapses within the prior 2 years, or who had at least onegadolinium-enhancing (Gd-enhancing) lesion on a brain MRI within theprior 6 months or at baseline, wherein patients with primary progressiveMS were excluded, compared to the patients in the patient populationthat were administered a once daily 14 mg dosage of teriflunomide.Elements of the approved drug product are further defined in Example 4,Section 14, including Table 4 therein.

In particular embodiments of the approved drug product, the patients inthe patient population were treated for 108 weeks and ARR was reduced by30.5% compared to teriflunomide 14 mg.

Similarly, “label” or “drug product label” refers to informationprovided to a patient which provides relevant information regarding thedrug product. Such information includes, without limitation, one or moreof the description of the drug, clinical pharmacology, indications (usesfor the drug product), contraindication (who should not take the drugproduct), warnings, precautions, adverse events (side effects), drugabuse and dependence, dosage and administration, use in pregnancy, usein nursing mothers, use in children and older patients, how the drug issupplied, safety information for the patient, or any combinationthereof. In certain embodiments, the label or drug product labelprovides an instruction for use in a patient requiring multiplesclerosis medication. In further embodiments, the label or drug productlabel identifies ponesimod and provides instructions for its use in apatient requiring multiple sclerosis medication.

The term “reference listed drug” or “RLD” as used herein refers to adrug product to which new generic versions are compared to show thatthey are bioequivalent. It is also a medicinal product that has beengranted marketing authorization by a member state of the European Unionor by the Commission on the basis of a completed dossier, i.e., with thesubmission of quality, pre-clinical and clinical data in accordance withArticles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which theapplication for marketing authorization for a generic/hybrid medicinalproduct refers, by demonstration of bioequivalence, usually through thesubmission of the appropriate bioavailability studies.

In the United States, a company seeking approval to market a genericequivalent must refer to the RLD in its Abbreviated New Drug Application(ANDA). For example, an ANDA applicant relies on the FDA's finding thata previously approved drug product, i.e., the RLD, is safe andeffective, and must demonstrate, among other things, that the genericdrug product is the same as the RLD in certain ways. Specifically, withlimited exceptions, a drug product for which an ANDA is submitted musthave, among other things, the same active ingredient(s), conditions ofuse, route of administration, dosage form, strength, and (with certainpermissible differences) labeling as the RLD. The RLD is the listed drugto which the ANDA applicant must show its ANDA drug product is the samewith respect to active ingredient(s), dosage form, route ofadministration, strength, labeling and conditions of use, among othercharacteristics. In the electronic Orange Book, there is a column forRLDs and a column for reference standards. In the printed version of theOrange Book, the RLDs and reference standards are identified by specificsymbol.

A reference standard is the drug product selected by FDA that anapplicant seeking approval of an ANDA must use in conducting an in vivobioequivalence study required for approval. FDA generally selects asingle reference standard that ANDA applicants must use in in vivobioequivalence testing. Ordinarily, FDA will select the reference listeddrug as the reference standard. However, in some instances (e.g., wherethe reference listed drug has been withdrawn from sale and FDA hasdetermined it was not withdrawn for reasons of safety or effectiveness,and FDA selects an ANDA as the reference standard), the reference listeddrug and the reference standard may be different.

FDA identifies reference listed drugs in the Prescription Drug Product,OTC Drug Product, and Discontinued Drug Product Lists. Listed drugsidentified as reference listed drugs represent drug products upon whichan applicant can rely in seeking approval of an ANDA. FDA intends toupdate periodically the reference listed drugs identified in thePrescription Drug Product, OTC Drug Product, and Discontinued DrugProduct Lists, as appropriate.

FDA also identifies reference standards in the Prescription Drug Productand OTC Drug Product Lists. Listed drugs identified as referencestandards represent the FDA's best judgment at this time as to theappropriate comparator for purposes of conducting any in vivobioequivalence studies required for approval.

In some instances when FDA has not designated a listed drug as areference listed drug, such listed drug may be shielded from genericcompetition. If FDA has not designated a reference listed drug for adrug product the applicant intends to duplicate, the potential applicantmay ask FDA to designate a reference listed drug for that drug product.

FDA may, on its own initiative, select anew reference standard whendoing so will help to ensure that applications for generic drugs may besubmitted and evaluated, e.g., in the event that the listed drugcurrently selected as the reference standard has been withdrawn fromsale for other than safety and efficacy reasons.

In Europe, Applicants identify in the application form for itsgeneric/hybrid medicinal product, which is the same as an ANDA orsupplemental NDA (sNDA) drug product, the reference medicinal product(product name, strength, pharmaceutical form, marketing authorizationholder (MAH, first authorization, Member State/Community), which issynonymous with a RLD, as follows:

1. The medicinal product that is or has been authorized in the EuropeanEconomic Area (EEA), used as the basis for demonstrating that the dataprotection period defined in the European pharmaceutical legislation hasexpired. This reference medicinal product, identified for the purpose ofcalculating expiry of the period of data protection, may be for adifferent strength, pharmaceutical form, administration route orpresentation than the generic/hybrid medicinal product.

2. The medicinal product, the dossier of which is cross-referred to inthe generic/hybrid application (product name, strength, pharmaceuticalform, MAH, marketing authorization number). This reference medicinalproduct may have been authorized through separate procedures and under adifferent name than the reference medicinal product identified for thepurpose of calculating expiry of the period of data protection. Theproduct information of this reference medicinal product will, inprinciple, serve as the basis for the product information claimed forthe generic/hybrid medicinal product.

3. The medicinal product (product name, strength, pharmaceutical form,MAH, Member State of source) used for the bioequivalence study(ies)(where applicable).

The different abbreviated approval pathways for drug products under theFood, Drug, and Cosmetics (FD&C) Act are the abbreviated approvalpathways described in sections 505(j) and 505(b)(2) of the FD&C Act (21U.S.C. 355(j) and 21 U.S.C. 23 355(b)(2), respectively).

According to the FDA (“Determining Whether to Submit an ANDA or a505(b)(2) Application Guidance for Industry,” U.S. Department of Healthand Human Services, October 2017, pp. 1-14, the contents of which isincorporated herein by reference), NDAs and ANDAs can be divided intothe following four categories:

(1) A “stand-alone NDA” is an application submitted under section505(b)(1) and approved under section 505(c) of the FD&C Act thatcontains full reports of investigations of safety and effectiveness thatwere conducted by or for the applicant or for which the applicant has aright of reference or use.

(2) A section 505(b)(2) application is an NDA submitted under section505(b)(1) and approved under section 505(c) of the FD&C Act thatcontains full reports of investigations of safety and effectiveness,where at least some of the information required for approval comes fromstudies not conducted by or for the applicant and for which theapplicant has not obtained a right of reference or use.

(3) An ANDA is an application for a duplicate of a previously approveddrug product that was submitted and approved under section 505(j) of theFD&C Act. An ANDA relies on the FDA's finding that the previouslyapproved drug product, i.e., the reference listed drug (RLD), is safeand effective. An ANDA generally must contain information to show thatthe generic product (a) is the same as the RLD with respect to theactive ingredient(s), conditions of use, route of administration, dosageform, strength, and labeling (with certain permissible differences) and(b) is bioequivalent to the RLD. An ANDA may not be submitted if studiesare necessary to establish the safety and effectiveness of the product.

(4) A petitioned ANDA is a type of ANDA for a drug product that differsfrom the RLD in its dosage form, route of administration, strength, oractive ingredient (in a product with more than one active ingredient)and for which FDA has determined, in response to a petition submittedunder section 505( )(2)(C) of the FD&C Act (suitability petition), thatstudies are not necessary to establish the safety and effectiveness ofthe drug product.

A scientific premise underlying the Hatch-Waxman Act is that a drugproduct approved in an ANDA under section 505(j) of the FD&C Act ispresumed to be therapeutically equivalent to its RLD. Productsclassified as therapeutically equivalent can be substituted with thefull expectation that the substituted product will produce the sameclinical effect and safety profile as the prescribed product whenadministered to patients under the conditions specified in the labeling.In contrast to an ANDA, a section 505(b)(2) application allows greaterflexibility as to the characteristics of the product. A section505(b)(2) application will not necessarily be rated therapeuticallyequivalent to the listed drug it references upon approval.

The term “therapeutically equivalent to a reference listed drug” meansthat the drug product is a generic equivalent, i.e., pharmaceuticalequivalents, of the reference listed drug product and, as such, is ratedan AB therapeutic equivalent to the reference listed drug product by theFDA whereby actual or potential bioequivalence problems have beenresolved with adequate in vivo and/or in vitro evidence supportingbioequivalence.

“Pharmaceutical equivalents” means drug products in identical dosageforms and route(s) of administration that contain identical amounts ofthe identical active drug ingredient as the reference listed drug.

FDA classifies as therapeutically equivalent those products that meetthe following general criteria: (1) they are approved as safe andeffective; (2) they are pharmaceutical equivalents in that they (a)contain identical amounts of the same active drug ingredient in the samedosage form and route of administration, and (b) meet compendial orother applicable standards of strength, quality, purity, and identity;(3) they are bioequivalent in that (a) they do not present a known orpotential bioequivalence problem, and they meet an acceptable in vitrostandard, or (b) if they do present such a known or potential problem,they are shown to meet an appropriate bioequivalence standard; (4) theyare adequately labeled; and (5) they are manufactured in compliance withCurrent Good Manufacturing Practice regulations

The term “bioequivalent” or “bioequivalence” is the absence of asignificant difference in the rate and extent to which the activeingredient or active moiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available at the site of drug actionwhen administered at the same molar dose under similar conditions in anappropriately designed study. Section 505 (j)(8)(B) of the FD&C Actdescribes one set of conditions under which a test and reference listeddrug shall be considered bioequivalent:

the rate and extent of absorption of the [test] drug do not show asignificant difference from the rate and extent of absorption of the[reference] drug when administered at the same molar dose of thetherapeutic ingredient under similar experimental conditions in either asingle dose or multiple doses; or

the extent of absorption of the [test] drug does not show a significantdifference from the extent of absorption of the [reference] drug whenadministered at the same molar dose of the therapeutic ingredient undersimilar experimental conditions in either a single dose or multipledoses and the difference from the [reference] drug in the rate ofabsorption of the drug is intentional, is reflected in its labeling, isnot essential to the attainment of effective body drug concentrations onchronic use, and is considered medically insignificant for the drug.

Where these above methods are not applicable (e.g., for drug productsthat are not intended to be absorbed into the bloodstream), otherscientifically valid in vivo or in vitro test methods to demonstratebioequivalence may be appropriate.

For example, bioequivalence may sometimes be demonstrated using an invitro bioequivalence standard, especially when such an in vitro test hasbeen correlated with human in vivo bioavailability data. In othersituations, bioequivalence may sometimes be demonstrated throughcomparative clinical trials or pharmacodynamic studies.

The methods may also comprise, consist of, or consist essentially ofselling or offering to sell ponesimod into the stream of commerce.

Clinical Management Events

As noted herein, sphingosine-1-phosphate receptor modulators (SIPs), aclass of oral disease, modifying therapies (DMTs) for multiple sclerosis(MS), are cell-trafficking inhibitors that have been shown to have highefficacy. There are at least four S1Ps that are indicated for MS in theUnited States: fingolimod, siponimod, ozanimod, and ponesimod. Althoughthese S1Ps share some similarities as a class, the individual S1Ps havedifferences in selectivity for receptor subtypes and phosphorylationrequirements, half-lives, and safety profiles that result in differentclinical requirements before and after treatment initiation. Someclinical management events are common across the SIPs, such as completeblood count, electrocardiogram, and liver function tests beforetreatment initiation. However, each SIP also has unique recommendationsfor clinical management events described in their US PrescribingInformation (USPI), which may impact their overall ease of use. S1Pswith fewer clinical management events may be easier to use than thosethat require more monitoring.

As used herein, clinical management events refer to management ofpotential or actual events that may require medical intervention. Asdescribed herein, clinical management events prior to initiation oftreatment include, for example, first-dose monitoring, genotyping,and/or an eye exam. After initiation, events include, for example,drug-drug interactions (DDI), eye exam, and/or liver function tests.

The disclosure provides methods for reducing clinical management eventsbefore or during treatment of multiple sclerosis in a patient in needthereof, comprising administering ponesimod in an amount and manner thatis described in a drug product label for an approved product and/or in atreatment regimen described herein, namely administration of about 20 mgof ponesimod orally once daily, with or without utilization of theup-titration dosing procedure also described herein. The reduction andease of use are relative to a patient population at substantially thesame level of disease progression receiving a standard of care treatmentcomprising an S1P receptor modulator other than ponesimod, including,for example, fingolimod, siponimod, and ozanimod (see Example 3).

Other Aspects of the Disclosure

Beta blockers, also known as beta-adrenergic blocking agents, are widelyused medications to reduce blood pressure and may be co-administered inMS patients. Concomitant use of ponesimod and drugs that decrease heartrate may be result in bradycardia and heart block. As a result, cautionshould be applied when ponesimod is initiated in patients receivingtreatment with a beta-blocker because of the additive effects onlowering heart rate. In certain embodiments, for patients receiving astable dose of a beta-blocker, the resting heart rate should beconsidered before introducing ponesimod treatment. If the resting heartrate is greater than 55 bpm under chronic beta-blocker treatment,ponesimod can be introduced. If the resting heart rate is less than orequal to 55 bpm, beta-blocker treatment should be interrupted until thebaseline heart rate is greater than 55 bpm. In this case, treatment withponesimod can then be initiated and treatment with a beta-blocker can bereinitiated after ponesimod has been up-titrated (via the 14-daytitration regimen) to the target maintenance dosage.

For example, the negative chronotropic effect of coadministration ofponesimod and propranolol was evaluated in a dedicated pharmacodynamicssafety study. In particular, the 14-day dose titration regimen ofponesimod was administered to subjects receiving propranolol (80 mg)once daily. As noted in Example 4, no significant changes inpharmacokinetics of ponesimod or propranolol were observed.

In particular embodiments, where a patient is being treated with abeta-blocker and ponesimod treatment is to be initiated, and wherein thepatient has a resting heart rate of greater than 55 beats per minuteduring treatment with the beta-block and prior to initiation ofponesimod, ponesimod is administered without interruption to thebeta-blocker treatment. In other embodiments, where a patient is beingtreated with a beta-blocker and ponesimod treatment is to be initiated,and wherein the patient has a resting heart rate of less than or equalto 55 beats per minute during treatment with the beta-block and prior toinitiation of ponesimod, beta-blocker treatment is interrupted until thepatient's heart rate is greater than 55 beats per minute and ponesmodtreatment is initiated in a titration regimen comprising administeringorally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimodon days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod onday 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg ofponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimodon days 12, 13, and 14, followed by administering a 20 mg maintenancedose of ponesimod once daily thereafter, and the beta-blocker isreinitiated after ponesimod has been up-titrated to the maintenancedosage.

Because initiation of ponesimod treatment results in a decrease in heartrate (HR), first-dose 4-hour monitoring is also recommended for patientswith sinus bradycardia (HR less than 55 beats per minute (bpm)), first-or second-degree (Mobitz type I) AV block, or a history of myocardialinfarction or heart failure occurring more than 6 months prior totreatment initiation and in stable condition. As part of the first dose4-hour monitoring, a first dose of ponesimod (e.g. 2 mg of ponesimod aspart of the titration regimen) is administered in a setting whereresources to appropriately manage symptomatic bradycardia are available.Patients are to be monitored for 4 hours after the first dose for signsand symptoms of bradycardia with pulse and blood pressure measurements,preferably with a minimum of hourly measurements. Further, in additionalembodiments, an electrocardiogram (ECG) is obtained for these patientsprior to dosing and at the end of the 4-hour observation period.

Accordingly, methods include treating multiple sclerosis in a patient inneed thereof, wherein the patient has sinus bradycardia, first or seconddegree AV block, or a history of myocardial infarction or heart failureoccurring more than 6 months prior to the initiation of ponesimodtreatment, comprising administering an effective regimen of ponesimod tothe patient, wherein after a first dose of the ponesimod, the patient ismonitored for a period of 4 hours for symptoms of bradycardia. In otherembodiments, no first dose monitoring is needed wherein the patient hasno sinus bradycardia, no first or second degree AV block, and no historyof myocardial infarction or heart failure occurring more than 6 monthsprior to the initiation of ponesimod treatment.

If any abnormalities are present after four hours, even in the absenceof symptoms, monitoring may be continued until the abnormality resolves.Abnormalities include, for example, a heart rate 4 hours post-dose thatis less than 45 bpm; a heart rate 4 hours post-dose that is at thelowest value post-dose, suggesting that the maximum pharmacodynamiceffect on the heart may not have occurred; and/or an ECG 4 hourspost-dose that shows new onset second-degree or higher AV block.

If post-dose symptomatic bradycardia, bradyarrhythmia, or conductionrelated symptoms occur, or if ECG 4 hours post-dose shows new onsetsecond degree or higher AV block or QTc greater than or equal to 500msec, appropriate management actions can be initiated. For example, thepatient can begin continuous ECG monitoring, and can otherwise bemonitored until the symptoms have resolved if no pharmacologicaltreatment is required. If pharmacological treatment is required, thepatient can be continued to be monitored, including overnight, and the4-hour monitoring can be repeated after the second dose of ponesimod.

In other embodiments, where patients have a preexisting heart and/orcerebrovascular condition; a prolonged QTc interval before dosing orduring the 4-hour observation, or at additional risk for QTprolongation, or on concurrent therapy with QT prolonging drug with aknown risk of torsades de pointes; and/or receiving concurrent therapywith drugs that slow heart rate or AV conduction, advice from acardiologist should be sought to determine the most appropriatemonitoring strategy, which can include, for example, overnightmonitoring during treatment initiation.

Although interruption during treatment is not preferred, this disclosureis also related to reinitiating ponesimod after treatment interruption.For example, if fewer than 4 consecutive doses are missed duringtitration, treatment is resumed with the first missed titration dose andthe titration schedule is resumed as that dose and titration day. Iffewer than 4 doses are missed during maintenance, treatment is resumedwith the maintenance dose. If 4 our more consecutive doses are missedduring titration or maintenance, treatment is reinitiated with Day 1 ofthe 14 day titration regimen, with first dose monitoring as describedherein for those patients needing such monitoring.

In other embodiments, use or concomitant use of certain drugs withponesimod should be contraindicated, avoided, or discontinued. Forexample, methods include treating multiple sclerosis in a patient inneed thereof, comprising administering an effective regimen of ponesimodto the patient wherein the treatment further comprises avoiding,contradicting, or discontinuing concomitant use of alemtuzumab. Othermethods include treating multiple sclerosis in a patient in needthereof, comprising administering an effective regimen of ponesimod tothe patient wherein the treatment further comprises avoiding,contradicting, or discontinuing concomitant use of QT prolonging drugswith known arrhythmogenic properties, heart rate lowering calciumchannel blockers (such as, for example, verapamil or diltiazem), orother drugs that reduce heart rate (such as, for example, digoxin).Additional methods include treating multiple sclerosis in a patient inneed thereof, comprising administering an effective regimen of ponesimodto the patient wherein the treatment further comprises avoiding,contradicting, or discontinuing concomitant use of strong CYP3A4 andUGT1A1 inducers (such as, for example, rifampin, phenytoin, orcarbamazepine) that decrease systemic exposure of the ponesimod.

Aspects of the Disclosure—the present disclosure pertains to andincludes at least the following additional aspects:

1. A method for treating multiple sclerosis in a patient in needthereof, comprising administering an approved drug product comprisingponesimod in an amount and manner that is described in a drug productlabel for the approved drug product.

2. The method of aspect 1, wherein about 20 mg of ponesimod isadministered orally once daily

3. The method of aspect 1 or aspect 2, wherein the treatment comprisesan up-titration step at initiation of the method or upon re-initiationof the method after a discontinuation, comprising administering orallyonce daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7;6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg ofponesimod on day 10; and 9 mg of ponesimod on day 11; 10 mg of ponesimodon days 12, 13, and 14, followed by administering 20 mg of ponesimodonce daily thereafter.

4. The method of any one of aspects 1-3, wherein the multiple sclerosisis relapsing multiple sclerosis.

5. The method of aspect 4, wherein the relapsing multiple sclerosiscomprises relapsing-remitting disease, clinically isolated syndrome, oractive secondary progressive disease.

6. A method of selling an approved drug product comprising ponesimod,said method comprising selling such drug product, wherein a drug productlabel for a reference listed drug for such drug product includesinstructions for treating a patient with multiple sclerosis.

7. A method of offering for sale a drug product comprising ponesimod,said method comprising offering for sale such drug product, wherein adrug product label for a reference listed drug for such drug productincludes instructions for treating a patient with multiple sclerosis.

8. The method of aspect 6 or aspect 7, wherein the drug product is anANDA drug product, a supplemental New Drug Application drug product, ora 505(b)(2) drug product.

9. A pharmaceutical product comprising ponesimod, wherein thepharmaceutical product is packaged, and wherein the package includes alabel that identifies ponesimod as an approved drug product for thetreatment of multiple sclerosis.

10. A method for treating multiple sclerosis in a patient in needthereof, comprising administering an effective regimen of ponesimod tothe patient wherein the treatment further comprises avoiding,contradicting, or discontinuing concomitant use of alemtuzumab.

11. A method for treating multiple sclerosis in a patient in needthereof, comprising administering an effective regimen of ponesimod tothe patient wherein the treatment further comprises avoiding,contradicting, or discontinuing concomitant use of QT prolonging drugswith known arrhythmogenic properties, heart rate lowering calciumchannel blockers (such as, for, example, verapamil or diltiazem), orother drugs that reduce heart rate (such as, for example, digoxin).

12. A method for treating multiple sclerosis in a patient in needthereof, comprising administering an effective regimen of ponesimod tothe patient wherein the treatment further comprises avoiding,contradicting, or discontinuing concomitant use of strong CYP3A4 andUGT1A1 inducers (such as, for example, rifampin, phenytoin, orcarbamazepine) that decrease systemic exposure of the ponesimod.

The following Examples are provided to illustrate some of the conceptsdescribed within this disclosure. While the Examples are considered toprovide an embodiment, it should not be considered to limit the moregeneral embodiments described herein

Example A: Fatigue Symptoms and Impact Questionnaire—Relapsing MultipleSclerosis (FSIQ-RMS)

The patient-reported outcome questionnaire used for the below Examplesis the Fatigue Symptoms and Impact Questionnaire—Relapsing MultipleSclerosis (FSIQ-RMS). The FSIQ-RMS is an MS specific 20-item PRO measurethat comprises 2 domains: one measuring MS symptoms (7 items) and onemeasuring MS-related impacts (13 items). The 7 symptom items and 13impact items (in 3 impacts subdomains: physical, cognitive andemotional, and coping) are presented below.

MS Symptoms Domain—7 Items

For the MS symptoms domain, the FSIQ-RMS asks about a patient'sfatigue-related symptoms of relapsing MS over the past 24 hours whiledoing routine daily activities (e.g., housework, yard work, shopping,working, etc.) for Items 1-6 or while at rest (e.g., reading a book,watching TV, etc.) for Item 7. Patients are asked to select a responseon a scale of 0 to 10 that best describes their experience and are askedto not skip any questions, with no answers being right or wrong.

MS-Related Impacts—13 Items

For the MS-related impacts domain, the FSIQ-RMS asks about how apatient's life was affected by fatigue-related symptoms of relapsing MSin the past 7 days. Patients are asked to select a response on a scaleof 0 to 4 that best describes their experience and are asked to not skipany questions, with no answers being right or wrong.

Example 1 Study Design

A prospective, multicenter, randomized, double-blind, active controlled,parallel-group, phase III, superiority study was conducted. The studywas designed to compare the efficacy, safety, and tolerability ofponesimod 20 mg vs teriflunomide 14 mg in adult subjects with relapsingMS.

Randomization: Subjects were randomized in a 1:1 ratio to ponesimod 20mg or teriflunomide 14 mg, stratified by prior use of MS diseasemodifying treatment (DMT) in the last two years prior to randomization(yes, no) and by baseline expanded disability status scale (EDSS) score(EDSS ≤3.5, EDSS >3.5).

Inclusion Criteria

This study enrolled adult male and female subjects aged 18 to 55 yearswith established diagnosis of MS, as defined by the 2010 revision ofMcDonald Diagnostic Criteria [Polman C H, et al. Diagnostic criteria formultiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol.2011; 69(2):292-302], with relapsing course from onset (i.e.,relapsing-remitting multiple sclerosis and secondary progressivemultiple sclerosis [SPMS] with superimposed relapses). The trialincluded up to a maximum 15% of subjects with SPMS with superimposedrelapses.

Subjects had active disease evidenced by one or more MS attacks withonset within the period of 12 to 1 months prior to baseline EDSSassessment, or by two or more MS attacks with onset within the 24 to 1months prior to baseline EDSS assessment, or with one or moregadolinium-enhancing (Gd+) lesion(s) of the brain on an MRI performedwithin 6 months prior to baseline EDSS assessment. Enrolled subjectswere ambulatory with an EDSS score of up to 5.5 inclusive. The subjectswere treatment-naïve (i.e., no MS disease-modifying therapy received atany time in the past) or previously treated with interferon (IFN) β-1a,IFN β-1b, glatiramer acetate, dimethyl fumarate, or natalizumab.

Exclusion Criteria:

Subjects with significant medical conditions or therapies for suchconditions (e.g., cardiovascular, pulmonary, immunological, hepatic,ophthalmological, ocular) or lactating or pregnant women were noteligible to enter the study.

Subjects with contraindications to MRI or with clinically relevantmedical or surgical conditions that, in the opinion of the investigator,would put the subject at risk by participating in the study were noteligible to enter the study.

Study/Treatment Duration:

For an individual subject, the maximum duration of the study wasapproximately 118 weeks consisting of 6 weeks of screening, 108 weeks oftreatment and 4 weeks of safety follow-up. Subjects discontinuingtreatment prematurely had an option to stay in a post-treatmentobservation period (PTOP) for up to 108 weeks.

The study consisted of the following periods:

Pre-randomization period—Up to 45 days before randomization.

Treatment period: The double-blind treatment period lasted for 108weeks. It consisted of a randomization visit, visits at two, four, and12 weeks after randomization, and 12-weekly visits thereafter.

End-of-Treatment (EOT):

The EOT visit took place at Week 108 (or earlier in case of prematurediscontinuation of study drug). In all cases, the EOT visit took placeone day after the last dose of study drug but no later than 7 days afterthe last dose of study drug.

Subjects who completed treatment until Week 108 were eligible to enrollin an extension study conducted under a separate protocol. Subjects whodiscontinued study drug prematurely for any reason were not eligible forthe extension study.

Subjects who prematurely discontinued study drug treatment weresubsequently treated according to local standard of care at theinvestigator's discretion and were followed in the post-treatmentobservation period.

Post-Treatment Safety Follow-Up (Fu) Period:

Teriflunomide is eliminated slowly from plasma. An acceleratedelimination procedure was used by all subjects after the last dose ofstudy drug. A safety FU after the last dose of study drug was mandated.

All subjects entered the safety FU period:

For subjects who entered the extension study, the FU period startedafter the last dose of study drug and ended with a safety FU visit (FU1)14-22 days after the last dose of study drug or with an abbreviated FU223-37 days after the last dose of study drug (if compliance to theteriflunomide accelerated elimination procedure was assessed as notsufficient at FU1).

For subjects who did not enter the extension study, the safety FU periodlasted for 30 days after the last dose of study drug and included twosafety FU visits (FU1, FU2) at 14-22 and 30-37 days after the last doseof study drug, respectively.

Post-treatment observation period (PTOP):

Subjects who prematurely discontinued study treatment enter the PTOPwhich lasts until 108 weeks after randomization (i.e., planned EOTperiod). It consisted of an abbreviated schedule of assessments at thetime of the originally scheduled 12-weekly visits.

End-of-Study (EOS)

EOS was reached when treatment, safety FU, and, if applicable, PTOP havebeen completed.

For subjects who completed the 108-week treatment period and entered theextension study, the EOS visit corresponded to the FU visit (FU1)conducted 14-22 days after the last study drug dose or to theabbreviated FU2 visit conducted 23-37 days after the last study drugdose (if needed for compliance reasons with the teriflunomideaccelerated elimination procedure).

For all other subjects, the EOS visit corresponded to the 30-day FUvisit (FU2) or to the last visit of PTOP (i.e., Week 108 Visit of thePTOP), whichever was last.

Study Treatment:

The treatment period consisted of an up-titration period (from Day 1 to14) and a maintenance period (Day 15 until EOT).

During an initial phase of the study, the study drugs in theup-titration period were administered in a double-dummy fashion.Ponesimod (or matching placebo) was presented as tablet, andteriflunomide 14 mg (or matching placebo) was presented as capsule(i.e., daily administration of one tablet and one capsule). At a laterphase, the double-dummy material (tablet and capsule) was replaced bythe daily administration of one capsule containing either ponesimod orteriflunomide.

In the maintenance period, the study treatment consisted of the dailyadministration of one capsule containing ponesimod 20 mg orteriflunomide 14 mg.

To reduce the first-dose effect of ponesimod, an up-titration scheme wasimplemented from Day 1 to Day 14:

Days 1 and 2; 2 mg.

Days 3 and 4; 3 mg.

Days 5 and 6; 4 mg.

Day 7; 5 mg.

Day 8; 6 mg.

Day 9; 7 mg.

Day 10; 8 mg.

Day 11; 9 mg.

Days 12, 13, and 14; 10 mg.

Day 15 until EOT; 20 mg.

Primary analysis set for efficacy: The Full Analysis Set (FAS) includedall randomized subjects. Subjects were evaluated according to thetreatment they were randomized to.

Primary efficacy variable/primary timepoint: The primary endpoint wasannualized relapse rate (ARR) up to the end of study (EOS) defined asthe number of confirmed relapses per subject-year. All available data upto EOS, regardless of treatment discontinuation was included (ITTapproach).

Secondary efficacy variables and testing strategy: Four secondaryefficacy endpoints were analyzed as per the statistical testing strategyoutlined in FIG. 1 .

-   -   Change from baseline to Week 108 in fatigue-related symptoms as        measured by the symptoms domain of the FSIQ-RMS patient-reported        outcome [Fatigue]    -   Cumulative number of combined unique active lesions from        baseline to Week 108 on brain MRI [CUALs]    -   Time to first 12-week confirmed disability accumulation (CDA)        from baseline to EOS on Expanded Disability Status Scale (EDSS)        [12-week CDA]    -   Time to first 24-week CDA from baseline to EOS on EDSS [24-week        CDA]

See FIG. 1 for a schematic representation of the testing strategy.

The primary endpoint was powered with α=0.01. The secondary endpointstested with an overall α=0.05.

The sample size for the study was based on the primary endpoint anddetermined assuming a negative binomial distribution for number ofconfirmed relapses. A sample size of 1100 subjects (550 per treatmentarm) would provide a power of approximately 90% for a significance levelof 1%, under the assumption that ARR is 0.320 for teriflunomide 14 mgand 0.215 for ponesimod 20 mg (which corresponds to a rate ratio of0.67) and using a dispersion=0.9. An annual dropout rate ofapproximately 15% was assumed for the first year and 7.5% for the secondyear.

Statistical Methods

The Full Analysis Set (FAS) included all randomized subjects. In orderto adhere to the intention-to-treat principle as much as possible,subjects were evaluated according to the treatment they have beenrandomized to.

The Per-Protocol Set (PPS) comprises all subjects included in the FASwithout any major protocol deviations, that impact the assessment of theprimary/secondary endpoints, occurring prior to or at randomization.

The Safety Set (SAF) included all randomized subjects who received atleast one dose of study treatment. Subjects were analyzed based onactual treatment taken, not randomized treatment.

A generalized linear model with negative binomial distribution wasfitted for the primary efficacy endpoint ARR. Two-sided hypotheses wereexpressed in terms of the model parameters μP20 mg and μT14 mg. Theprimary null hypothesis was that the ARR (p) does not differ betweenponesimod 20 mg and teriflunomide 14 mg.

The null hypothesis was tested by a two-sided Wald test within thenegative binomial regression model with a two-sided significance levelof 0.01 for conclusive evidence and 0.05 for a positive study. Two-sided99% and 95% Wald confidence intervals were calculated for the relativereduction in mean ARR for ponesimod 20 mg compared to teriflunomide 14mg.

The primary statistical analysis of the ARR endpoint was performed onthe FAS using a negative binomial model for confirmed relapses, with thestratification variables prior use of disease-modifying therapies (DMTs)and EDSS category as well as the number of relapses in the year prior tostudy entry, included in the model and time in the study as an offsetvariable. Sensitivity analyses was performed on the PPS and also basedon different subgroups derived from baseline variables.

The secondary efficacy endpoints were tested if the primary analysis onARR leads to the rejection of the null hypothesis in favor of ponesimod20 mg at an overall two-sided significance level of 0.05. A fallbackmethod was used for testing the family of hypotheses related to thefollowing three secondary endpoints: Absolute change of FSIQ-RMS frombaseline to Week 108; Cumulative number of CUAL from baseline to Week108; Time to 12-week CDA from baseline up to EOS. This was followed in ahierarchical manner by testing Time to 24-week CDA from baseline up toEOS; at the remaining alpha.

The endpoints were analyzed using the FAS population. All secondaryendpoints were also analyzed using the PPS population.

Primary Objective

To determine whether ponesimod is more efficacious than teriflunomide interms of reducing relapses in subjects with RMS.

Results

Disposition and baseline characteristics: A total of 1133 subjects wererandomized to the study, 567 to ponesimod 20 mg and 566 to teriflunomide14 mg. Overall treatment and study discontinuation were balanced acrossboth treatment arms, 83% of subjects completed treatment. The mean agewas 36.7 years and 64.9% of subjects were female. Most subjects wererecruited in Europe with 50.6% from EU countries. Mean baseline EDSSscore was 2.6 and mean disease duration was 7.6 years. Mean pre-study12-month relapse rate was 1.3, and 42.6% subjects had >1gadolinium-enhancing (Gd+) T1 lesions. The treatment arms were generallybalanced in terms of demographics and baseline disease characteristics.

1. Subject And Treatment Information

A total of 1468 subjects were screened. Of those, 1133 subjects wererandomized (567 to ponesimod 20 mg and 566 to teriflunomide 14 mg)across 162 sites in 28 countries, and 1131 subjects received at leastone dose of study drug. The disposition of subjects is summarized inTable 1 and a summary of reasons (primary reason) for treatmentdiscontinuation are shown in Table 2. Overall treatment and studydiscontinuation were balanced across both treatment arms. A total of6.5% and 2.5% of the subjects discontinued due to AEs or tolerabilityrelated reasons in ponesimod 20 mg and teriflunomide 14 mg,respectively, while 1.9% and 4.3% discontinued due to efficacy relatedreasons. There were 2 deaths reported during the study—both onteriflunomide 14 mg.

1.1 Disposition and Treatment Discontinuation Information

TABLE 1 Disposition of subjects Analysis Set: Subjects screenedPonesimod Teriflunomide 20 mg 14 mg Total N = 567 N = 566 N = 1133 n (%)n (%) n (%) Subjects screened 1468 Subjects re-screened 110 Subjectsrandomized 567 (100) 566 (100) 1133 (100) Subjects randomized afterre-screening 47 (8.3) 36 (6.4) 83 (7.3) Subjects treated 565 (99.6) 566(100) 1131 (99.8) Subjects completed treatment as per protocol 471(83.1) 473 (83.6) 944 (83.3) Subjects completed study as per protocol490 (86.4) 495 (87.5) 985 (86.9) Subjects completed treatment and studyas per 465 (82.0) 465 (82.2) 930 (82.1) protocol Subjects stayed instudy beyond safety follow-up 67 (11.8) 62 (11.0) 129 (11.4) (PTOP)Percentages based on subjects randomized Safety follow-up is up to EOT +30 days. PTOP = Post-treatment observation period.

TABLE 2 Reasons for premature treatment discontinuation Analysis Set:Safety Set Ponesimod Teriflunomide 20 mg 14 mg Total N = 565 N = 566 N =1131 n (%) n (%) n (%) Subjects who prematurely 94 (16.6) 93 (16.4) 187(16.5) discontinued study treatment Reasons for prematurediscontinuation of study treatment Subject decision 39 (6.9) 49 (8.7) 88(7.8) Efficacy related 7 (1.2) 14 (2.5) 21 (1.9) Tolerability related 8(1.4) 5 (0.9) 13 (1.1) Other 19 (3.4) 26 (4.6) 45 (4.0) Not known 5(0.9) 4 (0.7) 9 (0.8) Physician decision 40 (7.1) 23 (4.1) 63 (5.6)Adverse event 29 (5.1) 9 (1.6) 38 (3.4) Lack of efficacy/treatmentfailure 4 (0.7) 10 (1.8) 14 (1.2) Other 7 (1.2) 4 (0.7) 11 (1.0)Pre-specified study treatment 12 (2.1) 16 (2.8) 28 (2.5) discontinuationcriteria Lost to follow-up 2 (0.4) 3 (0.5) 5 (0.4) Death 0 2 (0.4) 2(0.2) Reason not provided 1 (0.2) 0 1 (0.1)

1.2 Demographic and Baseline Characteristics

Randomization was stratified by prior-DMT in the last two years prior torandomization (yes: 39.5%; no: 60.5%) and EDSS score at baseline (≤3.583.3%; >3.5 16.7%). The mean age was 36.7 years and the majority ofsubjects (64.9%) were female. Most subjects were recruited in Europewith 50.6% from EU countries. Mean baseline EDSS score was 2.6, meandisease duration was 7.6 years and 97.4% were RRMS subjects. Meanpre-study 12-month relapse rate was 1.3, and 42.6% subjects had ≥1 Gd+T1lesions on brain MRI. The treatment arms were generally balanced interms of demographics and baseline disease characteristics (Tables 3 and4).

TABLE 3 Demographic characteristics Analysis Set: Full Analysis SetPonesimod Teriflunomide 20 mg 14 mg Total N = 567 N = 566 N = 1133 Sex[n (%)] N 567 566 1133 Male 204 (36.0) 194 (34.3) 398 (35.1) Female 363(64.0) 372 (65.7) 735 (64.9) Age (years) N 567 566 1133 Mean 36.7 36.836.7 SD 8.74 8.74 8.74 Median 36.0 37.0 37.0 Q1, Q3 30.0, 44.0 30.0,44.0 30.0, 44.0 Min, Max 18, 55 18, 55 18, 55 Race [n (%)] N 567 5661133 White 551 (97.2) 553 (97.7) 1104 (97.4) American Indian or AlaskaNative 0 1 (0.2) 1 (0.1) Black or African American 3 (0.5) 2 (0.4) 5(0.4) Other 5 (0.9) 2 (0.4) 7 (0.6) Not applicable 8 (1.4) 8 (1.4) 16(1.4) Geographical region/Country of enrolling site [n (%)] EuropeanUnion (EU) + UK 289 (51.0) 284 (50.2) 573 (50.6) Europe Non-EU + Russia233 (41.1) 239 (42.2) 472 (41.7) North America 32 (5.6) 24 (4.2) 56(4.9) Rest of World 13 (2.3) 19 (3.4) 32 (2.8)

TABLE 4 Baseline disease characteristics Analysis Set: Full Analysis SetPonesimod Teriflunomide 20 mg 14 mg Total N = 567 N = 566 N = 1133Baseline EDSS N 567 566 1133 Mean 2.57 2.56 2.56 SD 1.174 1.229 1.201Median 2.50 2.50 2.50 Q1, Q3 1.50, 3.50 1.50, 3.50 1.50, 3.50 Min, Max0.0, 5.5 0.0, 5.5 0.0, 5.5 Any DMT(a) received within 2 years prior toRandomization (eCRF) [n (%)] N 567 566 1133 Yes 213 (37.6) 211 (37.3)424 (37.4) No 354 (62.4) 355 (62.7) 709 (62.6) Time since first symptoms(years) at randomization N 567 566 1133 Mean 7.63 7.65 7.64 SD 6.7816.782 6.779 Median 5.84 5.70 5.77 Q1, Q3  2.40, 10.97  2.24, 11.03 2.32, 11.01 Min, Max  0.2, 40.8  0.2, 30.8  0.2, 40.8 Number ofrelapses in last year prior to study entry N 567 565 1132 Mean 1.2 1.31.3 SD 0.61 0.65 0.63 Median 1.0 1.0 1.0 Q1, Q3 1.0, 1.0 1.0, 2.0 1.0,1.0 Min, Max 0, 4 0, 5 0, 5 Multiple sclerosis subtype [n (%)] N 567 5661133 RRMS 552 (97.4) 552 (97.5) 1104 (97.4) SPMS 15 (2.6) 14 (2.5) 29(2.6) Presence of Gd + T1 lesions at baseline (from central reader) [n(%)] N 567 564 1131 Yes 226 (39.9) 256 (45.4) 482 (42.6) No 341 (60.1)308 (54.6) 649 (57.4) Volume of T2 lesions at baseline [mm3] (fromcentral reader) N 565 563 1128 Mean 8301.4 9489.2 8894.3 SD 10346.2811265.42 10826.32 Median 4841.3 5651.0 5171.7 Q1, Q3  1679.6, 11004.4 2022.9, 12978.7  1851.3, 11754.1 Min, Max   0, 86053   0, 82776   0,86053 Highly active disease [n (%)] N 567 566 1133 Yes 202 (35.6) 200(35.3) 402 (35.5) No 365 (64.4) 366 (64.7) 731 (64.5) (a)DMT = MSdisease-modifying treatment. RRMS = Relapsing-remitting multiplesclerosis, SPMS = Secondary progressive multiple sclerosis.

1.3 Extent of Exposure

The mean treatment exposure (irrespective of interruptions) was 96.7weeks in the ponesimod 20 mg arm and 97.5 weeks in the teriflunomide 14mg arm. The cumulative exposure to ponesimod 20 mg was 1045subject-years and was 1057 subject-years for teriflunomide 14 mg arm.

TABLE 5 Study treatment exposure Analysis Set: Safety Set PonesimodTeriflunomide 20 mg 14 mg N = 565 N = 566 Treatment exposure,irrespective of interruptions (weeks) N 564 566 Mean 96.69 97.45 SD29.018 27.022 Median 108.00 108.00 Q1, Q3 107.29, 108.71 107.29, 108.57Min, Max  0.3, 111.3  0.1, 113.0 Treatment exposure, irrespective ofinterruptions N 564 566 Cumulative exposure (years) 1045.2 1057.1Treatment exposure based on study drug log. Treatment duration onlypresented for subjects with available complete treatment end date.Interruptions derived based on study drug log and number of capsulestaken.

2. Primary Endpoint Analysis

Primary efficacy endpoint: Ponesimod 20 mg statistically significantlyreduced ARR (confirmed relapses) up to EOS by 30.5% compared toteriflunomide 14 mg (ARR=0.202 for ponesimod 20 mg vs. 0.290 forteriflunomide 14 mg, rate ratio: 0.695 [99% CL: 0.536: 0.902],p=0.0003). The primary endpoint results are robust, all sensitivity andsupplementary analyses are in line with the primary analysis.

A relapse is defined as new, worsening or recurrent neurologicalsymptoms that occur at least 30 days after the onset of a precedingrelapse, and that last at least 24 hours, in the absence of fever orinfection.

The new, worsening or recurrent neurological symptoms were evaluated bythe treating neurologist and, if all the elements of the abovedefinition were verified, and in the absence of another, betterexplanation of the subject's symptoms, the event was considered as arelapse. The onset date of the relapse corresponded to the onset date ofthe symptoms.

A relapse was confirmed by the treating neurologist only when thesubjects' symptoms were accompanied by an increase in EDSS/FS(functional system) scores, which were consistent with the subject'ssymptoms, from a previous clinically stable EDSS/FS assessment (i.e.,performed at least 30 days after the onset of any previous relapse),obtained by the efficacy assessor and consistent with the following:

-   -   An increase of at least half a step (0.5 points; unless EDSS=0,        then an increase of at least 1.0 points is required) or    -   An increase of at least 1.0 point in at least two FS scores, or    -   An increase of at least 2.0 points in at least one FS score        (excluding bladder/bowel and cerebral).

The primary statistical analysis was performed up to EOS on the FASusing a negative binomial regression model for confirmed relapses, withtreatment as a factor and the binary stratification variables (EDSS ≤3.5versus EDSS >3.5; DMTs within last 2 years prior to randomization[Yes/No]) and the number of relapses in the year prior to study entry(categories 5 1 (or missing) and ≥2) included in the model. The modelalso included an offset variable defined as the log of time on study (inyears) from randomization up to EOS.

Ponesimod 20 mg statistically significantly reduced ARR (confirmedrelapses) up to EOS by 30.5% compared to teriflunomide 14 mg (ARR=0.202for ponesimod 20 mg vs. 0.290 for teriflunomide 14 mg, rate ratio: 0.695[99% CL: 0.536: 0.902], p=0.0003).

The primary endpoint results were robust; all sensitivity (see FIG. 7 )and supplementary analyses (see FIG. 2A) are in line with the primaryanalysis. Subgroup analysis [see FIG. 8 ], shows most notably that thereappears to be a treatment-by-EDSS stratum interaction.

TABLE 6 Confirmed relapses up to EOS - ARR from negative binomialregression (Primary analysis) Analysis Set: Full Analysis Set PonesimodTeriflunomide 20 mg 14 mg N = 567 N = 566 Mean estimate (ARR) 0.2020.290 99% CL (0.165, 0.246) (0.244, 0.345) 95% CL (0.173, 0.235) (0.254,0.331) Treatment effect (rate ratio) 0.695 99% CL (0.536, 0.902) 95% CL(0.570, 0.848) p-value 0.0003 Dispersion estimate 0.765 Number ofsubjects included in 567 566 analysis Total number of relapses 242 344Total time (years) 1119 1137 Raw ARR 0.216 0.303

3. Secondary Endpoint(S) Main Analyses

3.1 Fatigue—Change from Baseline to Week 108 in FSIQ-RMS Weekly SymptomsScore

Change from baseline to Week 108 in the FSIQ-RMS weekly symptoms score,based on the full analysis set, was statistically significantly lower inthe ponesimod 20 mg arm compared with teriflunomide 14 mg, based on anMMRM analysis (mean=−0.01 for ponesimod 20 mg vs. 3.56 for teriflunomide14 mg, mean difference: −3.57 [95% CL: −5.83: −1.32J, p=0.0019, anincrease from baseline indicates worsening in fatigue symptoms). SeeFIG. 3A.

Cumulative distribution function of change is shown in FIG. 3B. Resultsof the study are summarized below in Table 6A. In addition to theobservation of statistical significance at the group level change frombaseline favoring ponesimod, there is also observed a statisticallysignificant difference in patients who were stable or improved onponesimod compared to teriflunomide. This suggests a statisticallysignificant and clinically meaningful difference for ponesimod at thepatient level.

TABLE 6A Summary of Change from Baseline to Week 108 for FSIQ- RMSWeekly Symptoms Score Based on Full Analysis Set. Change in FSIQ-RMS-S:Visit Total Score N Ponesimod N Teriflunomide P-Value Week 108 Improved(<−6.3) 105 30.5% 98 29.9% 0.5163 Stable (−6.3 < 132 38.4% 107 32.6% x <+6.3) Stable or Improved 237 68.9% 205 62.5% 0.045 Worsened (≥6.3) 10731.1% 123 37.5%

The FSIQ-RMS is an MS specific 20-item PRO measure that comprises 2domains: one measuring MS symptoms and one measuring MS-related impacts.The symptoms domain of the scale was used in this study to compare theeffect of ponesimod and teriflunomide on fatigue. This new tool has anumber of advantages compared to the available fatigue tools for MS. SeeHudgens S, et al., Development and Validation of the FSIQ-RMS: A NewPatient-Reported Questionnaire to Assess Symptoms and Impacts of Fatiguein Relapsing Multiple Sclerosis. Value Health. 2019 April;22(4):453-466. doi: 10.1016/j.jval.2018.11.007. Epub 2019 Feb. 21.PubMed PMID: 30975397. With 7 symptom items and 13 impact items (in 3impacts subdomains: physical, cognitive and emotional, and coping), theFSIQ-RMS is a comprehensive, valid, and reliable measure offatigue-related symptoms and impacts in RMS patients.

The FSIQ-RMS symptom domain (FSIQ-RMS-S) consists of seven itemsassessing fatigue-related symptoms with a recall period of 24 hoursmeasured on an 11-point numeric rating scale; the standardized symptomdomain score ranges from 0 to 100 with a higher score indicating greaterfatigue. This domain (i.e., section 1 of the questionnaire) is completedon 7 consecutive days.

The FSIQ-RMS impact domain (FSIQ-RMS-I) consists of 13 items assessingimpacts of fatigue-related symptoms with a recall period of 7 daysmeasured on a 5-point verbal descriptor scale, ranging from no impact toextreme impact; the impact domain score ranges from 0 to 100 with ahigher score indicating greater impact. As the impact domain of theFSIQ-RMS (i.e., section 2 of the questionnaire) has a 7-day recallperiod, it was completed on the last day (i.e., seventh day) ofcompletion of section 1.

FSIQ-RMS was completed during the pre-randomization period, at Visits 6,7, 10, and 12 (Weeks 12, 24, 60, 84), 14 (EOT), and at unscheduledvisits due to relapses (R1, R2, etc.) or other unscheduled visits (U1,U2, etc.) as described below. If applicable, FSIQ-RMS was performed atthe corresponding visits in the PTOP.

The completion of the FSIQ-RMS during the pre-randomization period wasdone as follows: At Visit 1 (Screening), subjects who appear eligiblebased on the assessments made during this visit (but prior to theresults from the laboratory assessments are received) were provided withthe electronic device containing the FSIQ-RMS.

Once the results from the laboratory assessments confirmed the subject'seligibility, and provided no other assessment performed in the meantimeexcluded the subject, the site coordinator contacted and asked thesubject to start the completion of the FSIQ-RMS. At home, the subjectcompleted the symptom domain of the FSIQ-RMS for 7 days (i.e., section 1of the questionnaire). On the seventh day, the subject completed theimpact domain of the FSIQ-RMS (i.e., section 2 of the questionnaire).The information captured from this assessment was used as the baselinedata for the FSIQ-RMS. Ideally, the FSIQ-RMS was completed during the 7consecutive days preceding the randomization.

After randomization, the symptoms domain of the FSIQ-RMS (i.e., section1 of the questionnaire) was completed by the subject at home on a dailybasis, starting in the evening of the day of a visit when the FSIQ-RMSwas administered (Day 1 of questionnaire administration cycle) andduring the 6 subsequent days (i.e., over 7 days in total). Subjectsreturned the completed FSIQ-RMS diary at the next scheduled visit. Onthe seventh day, the subject completed the impact domain of the FSIQ-RMS(i.e., section 2 of the questionnaire). If applicable, at the end of thePTOP, the FSIQ-RMS was completed prior to Visit 14A (Week 108), ideally,during the 7 consecutive days preceding the visit.

Results for the secondary endpoint of change from baseline to Week 108in the symptoms domain of the FSIQ-RMS (assessed over a 7-day period)have shown the superiority of ponesimod 20 mg over teriflunomide 14 mg.

3.2 MRI—Combined Unique Active Lesions (CUAL) from Baseline to Week 108.

CUAL are new Gd+T1 lesions plus new or enlarging T2 lesions (withoutdouble-counting of lesions).

The cumulative number of CUAL is considered a reliable outcome measureof inflammatory MS disease activity. Radiological evidence of diseaseactivity is routinely used to support disease diagnosis and to informtherapeutic decisions targeting no evidence of disease activity (NEDA),clinical (relapses or disability accumulation) or radiological (brainlesions on MRI) perspective. See Lublin F D. Disease activity freestatus in MS. Mult Scler Relat Disord. 2012 January; 1(1):6-7. doi:10.1016/j.msard.2011.08.001. Epub 2011 Aug. 27. PubMed PMID: 25876444.

MRI scans were performed at Visits 2 (Baseline), 10 (Week 60), and 14(EOT) and at any unscheduled visit (U1, U2, etc.). If applicable, MRIscans also were performed at the corresponding visits in the PTOP(Visits 10A and 14A). Testing at all visits were performed up to 7 daysprior to or after the visit date. In case of premature study treatmentdiscontinuation, the MRI at EOT did not need to be performed if the EOTvisit occurred within less than 4 weeks of the MRI assessment at Visit10 (Week 60).

MRI variables included the number and volume of new and total Gd+lesions on T1-weighted MRI scans, number of new and enlarging lesionsand lesion volume on T2-weighted MRI, and global measures of loss ofbrain tissue.

Lesion count of MRI performed within 24 months prior to the study wererecorded on the MS history page of the eCRF. These scans were notanalyzed by the medical image analysis center (MIAC).

T1-weighted imaging before and after i.v. administration of 0.1 mmol/kgbody weight (=0.2 mL/kg) of Gd as well as PD-T2-weighted imaging wasperformed. Gd may cause nausea and vomiting and in very rare casesallergic reactions that could require immediate anti-anaphylactictherapy (such as steroids, epinephrine/adrenaline, etc.).

Ponesimod 20 mg statistically significantly reduced by 56% the number ofCUALs between baseline and week 108 compared to teriflunomide 14 mg(mean CUALs per year=1.405 for ponesimod 20 mg vs. 3.164 forteriflunomide 14 mg, rate ratio: 0.44 [95% CL: 0.36: 0.54], p<0.0001). Atotal of 4.9% and 4.9% of subjects had a baseline but no post-baselineMRI; sensitivity analyses using a range of methods (data not shown) forimputation of missing data supported the primary results (p<0.0001 inall cases).

Ponesimod 20 mg was clearly superior in reducing the number of CUALs vsteriflunomide 14 mg, fully supporting and complementing the results ofthe primary endpoint.

TABLE 7 CUAL from baseline to Week 108 - negative binomial regression oflesions per year (Main analysis) Analysis Set: Full Analysis SetPonesimod Teriflunomide 20 mg 14 mg N = 567 N = 566 Mean estimate(Lesions per year) 1.405 3.164 95% CL (1.215, 1.624) (2.757, 3.631)Treatment effect (Rate Ratio) 0.444 95% CL (0.364, 0.542) p-value <0001Dispersion estimate 2.409 Number of subjects included in 539 536analysis Total number of lesions 1671 3714 Total time (years) 1072 1067Raw mean lesions/year 1.559 3.481 Mean estimate = CUAL per year, RateRatio: ponesimod vs. teriflunomide. Negative binomial model is appliedwith Wald confidence intervals and p-value. Offset: Log Time (years) upto last MRI scan. Covariates: EDSS strata (<=3.5, >3.5), DMT within last2 years prior to randomization strata (Y, N), and Gd+ T1 lesions atbaseline (absent or present). Subjects with baseline and at least onepost-baseline MRI are included in the analysis.

3.3 EDSS—Time to First 12-Week Confirmed Disability Accumulation (CDA)

The 12-week confirmed disability accumulation, also sometimes referredto as disability progression (CDA/CDP) is a common endpoint in RMSstudies, while 24-week CDA/CDP is regarded as the more robust andclinically relevant endpoint. See European Medicines Agency, Guidelineon clinical investigation of medicinal products for the treatment ofMultiple Sclerosis, 26 Mar. 2015, EMA/CHMP/771815/2011, Rev. 2,Committee for Medicinal Products for Human Use (CHMP). Teriflunomide 14mg has shown a statistically significant reduction in the risk of12-week CDP in the TEMSO and TOWER studies. See O'Connor P, et al. NEngl J Med. 2011; 365:1293-30; Confavreux C, et al.; TOWER Trial Group.Oral teriflunomide for patients with relapsing multiple sclerosis(TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Neurol. 2014 March; 13(3):247-56. doi:10.1016/S1474-4422(13)70308-9. Epub 2014 Jan. 23. PubMed PMID: 24461574.

A 12-week CDA is an increase of at least 1.5 in EDSS for subjects with abaseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS forsubjects with a baseline EDSS score of 1.0 to 5.0, or an increase of atleast 0.5 in EDSS for subjects with a baseline EDSS score ≥5.5 which isto be confirmed after 12 weeks.

Baseline EDSS is defined as the last EDSS score recorded prior torandomization. The initial EDSS increase, meeting the above criteria, isdefined as the onset of disability accumulation.

All EDSS measurements (with or without relapse, at a scheduled orunscheduled visit) were used to determine the onset of disabilityaccumulation. However, EDSS scores used for confirmation of disabilityaccumulation were obtained at a scheduled visit (i.e., unscheduledvisits cannot be used as confirmatory visits) outside any ongoingrelapse. In this context, relapse duration is defined as period betweenstart and end dates if available and limited to 90 days from onset ifend date is not available or duration is longer than 90 days.

In order to confirm that the EDSS increase is persistent, all EDSSmeasurements between the onset and the 12-week EDSS confirmation (minus7-day visit time-window) need to show an increase in EDSS, meeting thecriteria for accumulation of disability as defined above.

A 12-week CDA was observed in 10.1%, and 12.4% of subjects up to EOS inthe ponesimod 20 mg and teriflunomide 14 mg arms, respectively. The riskof 12-week CDA was not found to be statistically significantly differentfor ponesimod 20 mg as compared with teriflunomide 14 mg (hazard ratio:0.83 [95% CL, 0.58 to 1.18]; log-rank p=0.2939). Consequently, theformal testing procedure was stopped. See Table A3; see also FIG. 4 .

TABLE A3 Testing strategy: Overview of secondary endpoint resultsAnalysis Set: Full Analysis Set Effect Alpha Endpoint Measure Estimate95% CL available p-value Significant FSIQ-RMS Mean −3.57 −5.83, −1.320.0167 0.0019 Yes change from difference baseline to Week 108 CUAL fromRate ratio 0.44 0.36, 0.54 0.0333 <.0001 Yes baseline to Week 108 Timeto first Hazard ratio 0.83 0.58, 1.18 0.0500 0.2939 No 12-week CDA Timeto first Hazard ratio 0.84 0.57, 1.24 0.0000 0.3720 NA 24-week CDA CUAL= Combined unique active lesions; CDA = Confirmed disabilityaccumulation; NA = Not applicable. Effect measures display results ofPonesimod 20 mg vs. Teriflunomide 14 mg. Alpha available = Alphaavailable as per testing strategy for testing the correspondingendpoint.

3.4 EDSS—Time to First 24-Week Confirmed Disability Accumulation (CDA)

24-week CDA was not formally tested and only evaluated in an exploratorymanner. A 24-week CDA was observed in 8.1%, and 9.9% of subjects up toEOS in the ponesimod 20 mg and teriflunomide 14 mg arms, respectively.The risk of 24-week CDA for ponesimod 20 mg as compared withteriflunomide 14 mg was not found to be statistically significantlydifferent at a nominal α=0.05 (hazard ratio: 0.84 [95% CL, 0.57 to1.24]; log−rank p=0.3720). See FIG. 5 .

A 24-week CDA is an increase of at least 1.5 in EDSS for subjects with abaseline EDSS score of 0.0 or an increase of at least 1.0 in EDSS forsubjects with a baseline EDSS score of 1.0 to 5.0, or an increase of atleast 0.5 in EDSS for subjects with a baseline EDSS score >5.5 which isto be confirmed after 24 weeks.

Baseline EDSS is defined as the last EDSS score recorded prior torandomization. The initial EDSS increase, meeting the above criteria, isdefined as the onset of disability accumulation.

All EDSS measurements (with or without relapse, at a scheduled orunscheduled visit) were used to determine the onset of disabilityaccumulation. However, EDSS scores used for confirmation of disabilityaccumulation were obtained at a scheduled visit (i.e., unscheduledvisits cannot be used as confirmatory visits) outside any ongoingrelapse. In this context, relapse duration is defined as period betweenstart and end dates if available and limited to 90 days from onset ifend date is not available or duration is longer than 90 days.

In order to confirm that the EDSS increase is persistent, all EDSSmeasurements between the onset and the 24-week EDSS confirmation (minus7-day visit time-window) need to show an increase in EDSS, meeting thecriteria for accumulation of disability as defined above.

In this study, ponesimod 20 mg reduced by 17% and 16% the risk of 12-and 24-week CDA, respectively, compared to teriflunomide 14 mg, howeverthe difference did not reach statistical significance. This study wasnot powered for 12- or 24-week CDA, so results were not bound to bestatistically different.

4. Safety

4.1 Summary of All Adverse Events

An overview of treatment emergent AEs (TEAEs) is presented in Table 8.

TABLE 8 Overview of treatment-emergent adverse events (AE) Analysis Set:Safety Set Ponesimod Teriflunomide 20 mg 14 mg N = 565 N = 566Characteristic n (%) n (%) Subject with at least one AE 502 (88.8) 499(88.2) Severe AE 39 (6.9) 26 (4.6) Drug-Related AE 278 (49.2) 238 (42.0)AE leading to study drug 49 (8.7) 34 (6.0) discontinuation Serious AE 49(8.7) 46 (8.1) Fatal AE 0 2 (0.4)

Overall, the proportion of subjects who experienced at least one TEAEwas similar in both treatment arms (88.8% and 88.2% of subjects in theponesimod 20 mg and the teriflunomide 14 mg arms, respectively).

The most common TEAEs in the ponesimod 20 mg arm were ALT increased(19.5%), nasopharyngitis (19.3%), headache (11.5%) and upper respiratorytract infection (10.6%). The most common TEAEs in the ponesimod 20 mgarm were ALT increased (19.5% vs 9.4% in the teriflunomide arm),nasopharyngitis (19.3% vs 16.8%), headache (11.5% vs 12.7%) and upperrespiratory tract infections (10.6% vs 10.4%).

TEAEs leading to premature treatment discontinuation were reported in8.7% of ponesimod 20 mg subjects compared to 6.0% of teriflunomide 14 mgsubjects [see Table 9]. While the number of events was low, thedifference in the type of AEs leading to treatment discontinuation wasmainly driven by anticipated class effects on respiratory system andmacular edema. No infections led to permanent study treatmentdiscontinuation in the study.

TABLE 9 Treatment-emergent AEs leading to premature discontinuation ofstudy drug by SOC Analysis Set: Safety Set Ponesimod Teriflunomide 20 mg14 mg N = 565 N = 566 System Organ Class n (%) n (%) Subjects with atleast one AE 49 (8.7) 34 (6.0) Investigations 12 (2.1) 10 (1.8)Respiratory, thoracic and mediastinal 7 (1.2) 0 disorders Eye disorders5 (0.9) 0 Gastrointestinal disorders 4 (0.7) 4 (0.7) Blood and lymphaticsystem disorders 3 (0.5) 2 (0.4) General disorders and administration 3(0.5) 2 (0.4) site conditions Hepatobiliary disorders 3 (0.5) 2 (0.4)Pregnancy, puerperium and perinatal 3 (0.5) 3 (0.5) conditions Vasculardisorders 3 (0.5) 0 Nervous system disorders 2 (0.4) 4 (0.7) Socialcircumstances 2 (0.4) 1 (0.2) Cardiac disorders 1 (0.2) 2 (0.4)Musculoskeletal and connective tissue 1 (0.2) 1 (0.2) disordersNeoplasms benign, malignant and 1 (0.2) 1 (0.2) unspecified (incl cystsand polyps) Psychiatric disorders 1 (0.2) 1 (0.2) Skin and subcutaneoustissue disorders 1 (0.2) 2 (0.4) Reproductive system and breastdisorders 0 1 (0.2) Surgical and medical procedures 0 1 (0.2) SystemOrgan Classes are based on MedDRA version 21.0. SOCs are sorted bydescending order of frequency in the ponesimod arm.

There were two deaths reported in the study, one due to coronary arteryinsufficiency and one due to multiple sclerosis. Both deaths occurred insubjects receiving teriflunomide 14 mg.

The proportion of subjects who experienced at least one SAE was similarin both treatment arms (8.7% and 8.1% of subjects in the ponesimod 20 mgand the teriflunomide 14 mg arms, respectively).

An overview of AEs of special interest (AESIs) addressing anticipatedrisks of ponesimod is presented in Table 10. The most common AESIs werereported for category hepatobiliary disorders/liver enzyme abnormality(25.7% vs 14.5% in ponesimod 20 mg compared to teriflunomide 14 mg,respectively), followed by category hypertension (10.1% vs 9.0%/), andpulmonary events (8.0% vs 2.7%).

TABLE 10 Treatment-emergent AESIs by category Analysis Set: Safety SetPonesimod Teriflunomide 20 mg 14 mg N = 565 N = 566 AESI Category n (%)n (%) Hepatobiliary disorders/ 145 (25.7) 82 (14.5) Liver enzymeabnormality Hypertension 57 (10.1) 51 (9.0) Pulmonary events 45 (8.0) 15(2.7) Effect on heart rate and rhythm 29 (5.1) 24 (4.2) (includinghypotension) Herpetic infection 27 (4.8) 27 (4.8) Infection 9 (1.6) 5(0.9) Seizure 8 (1.4) 1 (0.2) Macular edema 6 (1.1) 1 (0.2) Skinmalignancy 5 (0.9) 1 (0.2) Non-skin malignancy 1 (0.2) 1 (0.2)Categories are sorted by descending order of frequency in the ponesimod20 mg arm. AESI - Adverse Event of Special Interest. Infection AESI areidentified by the AEs from the Infections and Infestations SOC, only ifreported as serious or severe.

The proportion of subjects who experienced ALT increase >3×ULN washigher in the ponesimod arm (17.3%) compared to teriflunomide (8.3%)whereas ALT increase >8×ULN was higher in the teriflunomide arm (2.1%)compared to ponesimod (0.7%). Based on the individual case review, mostALT/AST increases ≥3×ULN occurred as a single transient asymptomaticepisode, resolving with continued treatment or after protocol mandatedtreatment discontinuation. All but one case of bilirubin increase ≥2×ULNoccurred in subjects with pre-treatment bilirubin increases. One case ofpotential Hy's law occurred in a subject with pre-existing transaminaseelevation (ALT >5×ULN), and the event fully resolved within 2 weeksafter treatment discontinuation.

The incidence of treatment-emergent heart rate and rhythm (includinghypotension) AESIs on Day 1 was higher in the ponesimod 20 mg arm (2.1%)than in the teriflunomide 14 mg arm (0.4%). See Table 10A. However, theoverall incidence of first dose AESI on Day 1 was low (2.1%) inponesimod. None of these events were serious nor led to permanentdiscontinuation of study treatment. Discharge criteria at 4 hourspost-dose were met for ca. 99% of subjects. No 2nd or higher degree AVblock was observed. ECG HR effect: nadir at 2 hours post-dose(siponimod—3-4 hours, fingolimod—around by 6 hours). Low incidence oflow HR outliers (post-dose HR 5 40 bpm), all 3 of them with apre-treatment HR of ≤55 bpm, which is a known risk factor for post-dosebradycardia with S1P receptor modulators.

The mean heart rate reduction compared to pre-dose reached a maximum forponesimod 20 mg at 2-hours post dose, −8.7 bpm compared to −1.7 bpm forteriflunomide 14 mg (FIG. 6 ). There were 3 subjects with asymptomaticpost-dose HR ≤40 bpm in the ponesimod 20 mg arm (none on teriflunomide14 mg); all of these subjects had a pre-treatment HR <55 bpm, whichwould require post-dose monitoring according to regulatory precedence ofsiponimod [Mayzent® USPI].

TABLE 10A Treatment-emergent AESI by PT: Effect on heart rate and rhythm(including hypotension) on Day 1 Analysis Set: Safety Set PonesimodTeriflunomide 20 mg 14 mg N = 565 N = 566 Preferred Term n (%) n (%)Subjects with at least one AE 12 (2.1) 2 (0.4) Bradycardia 4 (0.7) 0Atrioventricular block first degree 3 (0.5) 0 Defect conductionintraventricular 2 (0.4) 0 Bundle branch block left 1 (0.2) 0 Bundlebranch block right 1 (0.2) 0 Sinus arrhythmia 1 (0.2) 0 Sinusbradycardia 1 (0.2) 0 Electrocardiogram QT prolonged 0 1 (0.2)Presyncope 0 1 (02) Preferred Terms are based on MedDRA version 21.0.Preferred terms are sorted by descending order of frequency in theponesimod arm. AESI - Adverse Event of Special Interest

Example 1A: FSIQ-RMS and Physical, Cognitive, and Coping Impact

Change from baseline to Week 108 for the physical, cognitive/emotionaland coping impacts sub-domains of FSIQ-RMS are shown in FIG. 9 , FIG. 10and FIG. 11 , respectively.

FIGS. 9, 10 and 11 show the FSIQ-RMS physical, cognitive/emotional andcoping impacts sub-domains at the group level, based on the fullanalysis set, for the ponesimod 20 mg treatment arm and theteriflunomide 14 mg treatment arm.

Example 1B: Change From Baseline to Week 108—Baseline Fatigue Below theMedian

Mean change from baseline to Week 108 in FSIQ-RMS weekly symptoms scorefor patients with baseline fatigue below the median is shown in FIG. 12. Cumulative distribution function of change is shown in FIG. 13 .Results are summarized in Table 11A below. Baseline fatigue (i.e.,weekly symptoms score at baseline) is provided in Table 11B and was usedfor the baseline fatigue below the median in this Example and thebaseline fatigue above the median in Example 1C.

Almost 65% of low baseline fatigue patients remained stable or improvedover the 108 weeks on ponesimod, as compared to about 55% over the 108weeks on teriflunomide.

TABLE 11A Change From Baseline to Week 108, Baseline Fatigue Below theMedian for Ponesimod and Teriflunomide Change From Baseline to Week 108:Baseline Fatigue Visit Below the Median N Ponesimod N TeriflunomideP-Value WEEK 108 Improved (<−6.3) 36 19.1% 34 20.9% 0.736 Stable (−6.3 <x < +6.3) 85 45.2% 55 33.7% Stable or Improved 121 64.4% 89 54.6% 0.088Worsened (≥6.3) 67 35.6% 74 45.4%

TABLE 11B Baseline fatigue (symptoms score of FSIQ at baseline).Ponesmiod Teriflunomide Minimum 0.0 0.0 Q1 14.49 17.93 Median 30.4130.71 Q3 46.33 46.33 Maximum 95.40 88.40

Example 1C: Change From Baseline to Week 108—Baseline Fatigue Above theMedian

Mean change from baseline to Week 108 in FSIQ-RMS weekly symptoms scorefor patients with baseline fatigue above the median is shown in FIG. 14. Cumulative distribution function of change is shown in FIG. 15 .

Example 1D: Change From Baseline to Week 108—Patients with No Prior DMTTreatment

Mean change from baseline to Week 108 in FSIQ-RMS weekly symptoms scorefor patients with no prior DMT treatment within about two years prior toinitiation of treatment is shown in FIG. 16 . Cumulative distributionfunction of change is shown in FIG. 17 . Results are summarized in Table12 below.

Patient improvement was clinically meaningful in 31.4% of patients onponesimod (P=0.052), and about 75% of patients on ponesimod remainedstable or improved by Week 108 (P=0.003).

TABLE 12 Change From Baseline to Week 108 in Patients with no Prior DMTTreatment for Ponesimod and Teriflunomide Change From Baseline to Week108: No Prior DMT Visit Treatment N Ponesimod N Teriflunomide P-ValueWeek 108 Improved (<−6.3) 65 31.4% 54 26.2% 0.052 Stable (−6.3 < x <+6.3) 91 44.0% 76 36.9% Stable or Improved 156 75.4% 130 63.1% 0.003Worsened (≥6.3) 51 24.6% 76 36.9%

Example 1E: Change From Baseline to Week 108 in Patients without Gd+T1Lesions at Baseline

Mean change from baseline to Week 108 for change in FSIQ-RMS weeklysymptoms score in patients without Gd+T1 lesions at baseline is shown inFIG. 18 . Cumulative distribution function of change is shown in FIG. 19. Results are summarized in Table 13 below.

Patients who had stable or improved symptoms of fatigue without baselineGd+T1 lesions demonstrated a statistically significant difference forponesimod compared to teriflunomide, about 68% for ponesimod vs. about57% for teriflunomide (p=0.021).

TABLE 13 Change From Baseline to Week 108 in Patients without Gd + T1Lesions at Baseline Change From Baseline to Week 108: No Gd + T1 VisitLesions N Ponesimod N Teriflunomide P-Value Week 108 Improved (<−6.3) 6130.0% 48 25.8% 0.257 Stable (−6.3 < x < +6.3) 76 37.4% 58 31.2% Stableor Improved 137 67.5% 106 57.0% 0.021 Worsened (≥6.3) 66 32.5% 80 43.0%

Example 1F: Change From Baseline to Week 108 in Patients with Gd+T1Lesions at Baseline

Mean change from baseline to Week 108 for change in FSIQ-RMS weeklysymptoms score in patients with Gd+T1 lesions at baseline is shown inFIG. 20 . Cumulative distribution function of change is shown in FIG. 21.

Example 1G: Change from Baseline to Week 108—Baseline EDSS ≤3.5

Mean change from baseline to Week 108 for change in FSIQ-RMS weeklysymptoms score for patients with lower baseline EDSS is shown in FIG. 22. Cumulative distribution function of change is shown in FIG. 23 .Results are summarized in Table 14 below.

TABLE 14 Change From Baseline to Week 108 in Patients with Baseline EDSS≤3.5 Change From Baseline to Week 108: Baseline Visit EDSS <3.5 NPonesimod N Teriflunomide P-Value Week 108 Improved (<−6.3) 90 30.6% 7527.9% 0.318 Stable (−6.3 < x < +6.3) 120 40.8% 92 34.2% Stable orImproved 210 71.4% 167 62.1% 0.010 Worsened (≥6.3) 84 28.6% 102 37.9%

Example 1H: Change From Baseline to Week 108—Patients with One or FewerPrior Relapses at Baseline

Mean change from baseline to Week 108 for change in FSIQ-RMS weeklysymptoms score for patients with one or fewer prior relapses at baselineis shown in FIG. 24 . Cumulative distribution function of change isshown in FIG. 25 .

Example 11: Change From Baseline to Week 108—Patients with Two or MorePrior Relapses at Baseline

Mean change from baseline to Week 108 for change in FSIQ-RMS weeklysymptoms score for patients with two or more prior relapses at baselineis shown in FIG. 26 . Cumulative distribution function of change isshown in FIG. 27 .

Example 2: Pre-Specified MRI Endpoints and No Evidence of DiseaseActivity (NEDA) Status

In this study, prespecified MRI-based endpoints and no evidence ofdisease activity (NEDA) status is evaluated.

Patients (18-55 years) with RMS (expanded disability status scalescores: 0-5.5) were randomized (1:1) to receive ponesimod (PON) 20 mg orteriflunomide (TER) 14 mg for 108 weeks. MRI assessments were: volume ofT2 lesions; mean number of new gadolinium-enhancing (Gd+) T1 lesions andnew/enlarging T2 lesions; and absence of active MRI lesions at week 108.NEDA-3 status (absence of confirmed relapse, Gd+T1 lesions andnew/enlarging T2 lesions on annual MRIs, and 12-week confirmeddisability accumulation) was evaluated from baseline to week 108.

A total of 985/1133 (86.9%) randomized patients completed the study. MRIfindings for PON vs TER from baseline to week 108, respectively, were:least square (LS) mean difference (PON-TER) in change from baseline intotal volume of T2 lesions: −399.2 mm³ (95% CLs:—651.5; —146.8,p=0.002); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (rateratio [RR]:0.42, 95% CLs:0.31; 0.56, p<0.0001); mean numbers ofnew/enlarging T2 lesions per year: 1.40 vs 3.16 (RR:0.44, 95% CLs:0.36;0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of newGd+T1 lesions: 2.18 (1.61; 2.95, p<0.0001) and absence of new/enlargingT2 lesions: 1.71 (1.30; 2.25, p=0.0001). At week 108, 28.2% (159/564)PON vs 18.3% (102/558) TER patients (OR: 1.70, CL:1.27; 2.28, p=0.0004)achieved NEDA-3. The most frequent reason for not achieving NEDA-3status at week 108 was presence of new/enlarging T2 lesions.

Patients treated with ponesimod demonstrated a higher proportion ofpatients achieving NEDA-3 status compared to those treated withteriflunomide.

Conclusions

This study demonstrates the superior efficacy of ponesimod over theactive control. Ibis study is the first study showing a statisticallysignificant effect on fatigue symptoms in a pre-defined secondaryendpoint (disease specific validated PRO), targeting a key unmet need.

This study also demonstrates that the safety profile of ponesimodappears to be consistent with previously observed safety findings withponesimod, and the known safety profile of other S1P receptormodulators. The gradual up-titration appears to successfully mitigatefirst-dose effects of ponesimod and supports forgoing first dosemonitoring for patients with no risk factors for symptomaticbradycardia.

Example 3—Clinical Management Introduction

Sphingosine-1-phosphate receptor modulators (SIPs), a class of oraldisease modifying therapies (DMTs) for multiple sclerosis (MS), arecell-trafficking inhibitors that have been shown to have high efficacy.

Four S1Ps are indicated for MS in the United States: fingolimod,siponimod, ozanimod, and ponesimod. Although these S1Ps share somesimilarities as a class, the individual SIPs have differences inselectivity for receptor subtypes and phosphorylation requirements,half-lives, and safety profiles that result in different clinicalrequirements before and after treatment initiation.

Some clinical management events are common across the S1Ps, such ascomplete blood count, electrocardiogram, and liver function tests beforetreatment initiation. However, each SIP also has unique recommendationsfor clinical management events described in their US PrescribingInformation (USPI), which may impact their overall ease of use. S1Pswith fewer clinical management events may be easier to use than thosethat require more monitoring.

Objective

The objective of this study was to estimate the expected frequencies ofdifferential clinical management events (eg, eye exam, first-dosecardiovascular monitoring, and drug-drug interactions [DDIs]) usingreal-world data sources of persons with MS; and to compare the use ofSCS for the treatment of relapses between ponesimod (PON) andteriflunomide (TER) groups in the OPTIMUM trial (See Example 1).

Methods Study Design

Retrospective cohort study utilized the following three USadministrative claims databases:

1) IBM® MarketScan® Commercial Claims and Encounters Database (IBMCCAE);

2) IBM® MarketScan® Medicare Supplemental and Coordination of BenefitsDatabase (IBM MDCR); and

3) Optum® Clinformatics® Extended Data Mart—Socioeconomic Status (OptumSES).

Analyses were performed on data converted to the Observational MedicalOutcomes Partnership Common Data Model, version 5.3.1.

Inclusion/exclusion criteria: claim for any MS DMT within the indexperiod (1 Jan. 2016-11 Mar. 2019) and no other demyelinating diseasediagnosis within 1 year before the index date. The index date wasdefined as follows:

-   -   1) For each patient, identify all DMT service dates within the        index period;    -   2) Retain DMT service dates with prior MS diagnosis between the        study period start date (1 Jan. 2015) and the DMT service date;    -   3) Retain DMT service dates that fall within a continuous        observation period spanning at least 1 year before and 1 year        after the DMT service date;    -   4) Retain DMT service dates on which patient is aged ≥18 years;        and    -   5) Of any remaining DMT service dates, select the earliest date        per patient as the index date.

Only differential events were quantified; common clinical managementevents that are applicable to all S1Ps were excluded from analysis,including complete blood count, Varicella zoster virus antibody testing,liver function tests (prior to S1P initiation), electrocardiogram,cancer screening, and pulmonary function tests.

Differential clinical management events prior to initiation werefirst-dose monitoring, genotyping, and an eye exam; after initiation,events were DDIs, eye exam, and liver function tests. The results aresummarized below in Table 15.

TABLE 15 Differential Clinical Management Events Up to or AfterTreatment Initiation Event Fingolimod Siponimod Ozanimod Ponesimod1^(st) Dose All Patients Recommended N/A Recommended Observation forPatients with for Patients with Certain Pre- Certain Pre- ExistingExisting Cardiac Cardiac Conditions Conditions Eye Exam All Patients AllPatients Recommended All Patients (Prior to for Patients withInitiation) History of Uveitis, Diabetes Mellitus or Macular OdemaGenotyping N/A All Patients N/A N/A (Prior to Initiation) DifferentialKetoconazole Moderate Adrenergic and Strong CYP3A4 DDIs (systemic)CYP2C9 serotonergic inducers, strong inhibitors, drugs, BCRP UGT1A1moderate inhibitors, inducers CYP2C9 MAO inducers inhibitors, strongCYP2C8 inducers, strong CYP2C8 inhibitors Eye Exam (3-4 All Patients N/AN/A N/A months after initiation) Periodic Liver All Patients N/A N/A N/AFunction Tests During Treatment S1P, sphingosine-1-phosphate receptormodulator; N/A, not available; DDI, drug-drug interaction; CYP,cytochrome 450; BCRP, breast cancer resistance protein; MAO, monoamineoxidase; UGT, UDP-glucuronosyltransferase. aAll S1Ps recommend an eyeexam at any time if there is any change in vision while on therapy andregular follow-up exams for patients with a history of diabetes oruveitis. Fingolimod differs in additionally requiring an exam 3 to 4months post initiation for all patients.

Endpoints/Outcomes

Total number of differential clinical management events (first-doseobservation, eye exam, DDIs) before and during the first year oftreatment for each S1P.

Prevalence of comorbidities for which a first-dose observation isrecommended prior to siponimod or ponesimod.

Prevalence of comorbidities (uveitis, macular oedema, diabetes mellitus)for which an eye exam is recommended prior to ozanimod.

Relative risk of DDIs among S1Ps (ie, number of drugs takenconcomitantly with any DMT for MS that would result in a DDI when takenwith an S1P [excluding DDIs common to all S1Ps]).

Identified were DDI types, removing all DDI classes common to the 4 SIPs(antineoplastic or immunosuppressive therapies, antiarrhythmic orQT-prolonging drugs, vaccines). Results are summarized below in Table16.

TABLE 16 USPI Drug Interactions Among S1Ps Interactions FingolimodSiponimod^(a) Ozanimod^(b) Ponesimod Antiarrhythmic drugs, QT- X X X Xprolonging drugs, drugs that slow heart rate^(c) Antineoplastic, immune-X X X X modulating, or immune- suppressive therapies Vaccinces X X X XAdrenergic and serotonergic X drugs (e.g., opioid drugs, SSRIs. SNRIs,TCAs, sympatho- mimetic drugs) BCRP Inhibitors X Lab TestInteraction^(d) X MAO Inhibitors X Moderate CYP2C9 Inducers X ModerateCYP2C9 Inhibitors X Strong CYP2C8 Inducers X Strong CYP2C8 Inhibitors XStrong CYP3A4 Inducers X Strong UGT1A1 Inducers X Systemic KetoconazoleX Tyramine^(d) X USPI, US Prescribing Information; S1P,sphingosine-1-phosphate receptor modulator; FIN, fingolimod; SIP,siponimod; OZA, ozanimod; PON, ponesimod; SSRI, selective serotoninreuptake inhibitor; SNRI, selective norepinephrine reuptake inhibitor;TCA, tricyclic antidepressant; BCRP, breast cancer resistance protein;MAO, monoamine oxidase; CYP, cytochrome 450; UGT,UDP-glucuronosyltransferase; DDI, drug-drug interaction. ^(a)For SIP: 1)Moderate or strong CYP3A4 inhibitors are specified as a DDI only whencombined with moderate CYP2C9 inhibitors; here, it is sufficient toidentify moderate CYP2C9 inhibitors (including moderate CYP2C9/CYP3A4dual inhibitors); 2) Strong CYP3A4 inducers are specified as a DDI onlywhen combined with moderate CYP2C9 inducers; here, it is sufficient toidentify moderate CYP2C9 inducers (including moderate CYP2C9/strongCYP3A4 dual inducers). ^(b)OZA's USPI lists CYP3A4 inhibitors andinducers as DDIs only when combined with other DDI types shown in thistable (eg, dual inducers). Thus, for this study, it was not necessary toinclude these as separate DDI types. ^(c)Purple highlighting indicatesdrug interactions that are common to all S1Ps. ^(d)Pharmacogenomic andlaboratory test interactions are not in scope for this study, andinteractions with foods and over-the-counter medications will not bedetectable in the databases.

Results

The majority of patients in all databases were female. The results aresummarized in Table 17.

TABLE 17 Cohorts Demographics in Each Database IBM IBM MDCR OPTUM SESCount 22,051 1,599 17,689 Female Patients, % 76 74 75 Age, Years, mean(SD) 48.0 (9.8) 67.9 (6.3) 52.8 (11.8) IBM CCAE, IBM ® MarketScan ®Commercial Claims and Encounters Database; IBM MDCR, IBM ® MarketScan ®Medicare Supplemental and Coordination of Benefits Database; Optum SES,Optum ® Clinformatics ® Extended Data Mart - Socioeconomic Status; SD,standard deviation.

In the IBM CCAE, ponesimod had the lowest number of differentialclinical management events (1.11) compared with fingolimod (4.00),siponimod (2.19), and ozanimod (1.85). The results are summarized inTable 4. Similar results were obtained in the IBM MDCR and Optum SESdatabases, as shown in FIG. 28 .

In FIG. 28 , the IBM CCAE, IBM® MarketScan® Commercial Claims andInsurance Database; IBM MDCR, IBM® MarketScan® Medicare Supplemental andCoordination of Benefits Database; Optum SES, Optum®® Clinformatics®Extended Data Mart—Socioeconomic Status. The differential events aremanagement events that have different recommendations for each SIP, suchas first-dose monitoring and eye exam.

TABLE 18 Estimated Number of Events of Differential Clinical ManagementEvents per Patient in the IBM CCAE Study Cohort Events FingolimodSiponimod Ozanimod Ponesimod 1^(st) Dose Monitoring 1 0.09 0 0.09 (dataon file for all MS patients) Eye Exam Before 1 1 0.09 1 IntitiationGenotyping 0 1 0 0 DDIs (average <0.01 0.10 1.76 0.02 number of S1P'sdifferential DDI drugs taken concomitantly with any MS DMT in a 1-yearperiod) Eye Exam, 3-4 1 0 0 0 Months After Initiation Periodic Liver 1 00 0 Function Tests, After Initiation Total 4.00 2.19 1.85 1.11(Events/Patient)

Per the USPI, first-dose monitoring is recommended for all patientsbefore fingolimod initiation. The cardiovascular risks described in theUSPIs for siponimod and ponesimod were observed in 9% of the IBM CCAEcohort. Thus, first-dose events were quantified as 1 per patient forfingolimod, 0.09 events per patient for siponimod and ponesimod, and 0events for ozanimod, as shown in Table 18.

An eye exam is recommended for all patients before fingolimod,siponimod, and ponesimod initiation. For ozanimod, 9% of the IBM CCAEcohort had conditions that trigger the recommendation for an eye exam,which translates into 0.09 events per patient for ozanimod and 1 eventper patient for the other S1Ps, as shown in Table 4.

In the IBM CCAE, the average number of DDI drugs used concomitantly withany MS DMTs within 1 year was 0.0005, 0.10, 1.76, and 0.02 forfingolimod, siponimod, ozanimod, and ponesimod, respectively, as shownin Table 4.

Per the USPI, periodic liver function tests are recommended duringfingolimod treatment, which was estimated as 1 event in the yearfollowing initiation, as shown in Table 4.

Limitations

The study design did not include exclusion criteria based oncontraindications for each S1P.

The study did not consider differences in recommended first-dosemonitoring durations (6 hours for fingolimod and siponimod vs 4 hoursfor ponesimod) or other differences, such as reversibility of lymphocytecounts.

Generalizability was limited because each database represents a specificpopulation of patients (eg, the IBM CCAE consists of commerciallyinsured individuals, whereas the IBM MDCR includes those who receivesupplemental Medicare coverage).

Administrative claims data lack clinical detail; a claim for a filledprescription does not indicate whether the medication was taken asprescribed and overlap of drug exposure dates (determined by overlap indrug supply by >1 day) may not reflect actual concomitant drug use.

Because of low sample sizes for newer agents, this analysis assessedrisk of DDIs (indicated as concomitant use with any MS DMT) rather thanactual DDIs for each S1P.

Conclusion

The data were consistent across different databases and suggestponesimod is expected to have the fewest clinical management eventsamong S1Ps and may be easier to use overall than other S1Ps

Example 4: Approved Drug Product Label Highlights of PrescribingInformation

These highlights do not include all the information needed to usePONVORY safely and effectively. See full prescribing information forPONVORY.

PONVORY™ (ponesimod) tablets, for oral use

Initial U.S. Approval: 2021

Indications and Usage

PONVORY is a sphingosine 1-phosphate receptor modulator indicated forthe treatment of relapsing forms of multiple sclerosis (MS), to includeclinically isolated syndrome, relapsing-remitting disease, and activesecondary progressive disease, in adults. (1

Dosage and Administration

Assessments are required prior to initiating PONVORY (2.1)

Titration is required for treatment initiation (2.2)

The recommended maintenance dosage is 20 mg taken orally once daily(2.2)

First-dose monitoring is recommended for patients with sinusbradycardia, first- or second-degree [Mobitz type I] atrioventricular(AV) block, or a history of myocardial infarction or bean figure (2.3)

Dosage Forms and Strengths

Tablets: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20mg (3)

Contraindications

In the last 6 months. experienced myocardial infarction, unstableangina, stroke transient ischemic attack (TIA), decompensated heartfailure requiring hospitalization, or Class III/IV heart failure (4)

Presence of Mobitz type II second-degree, third-degree AV block, or sicksinus syndrome, unless patient has a functioning pacemaker (4)

Warnings and Precautions

Infections: PONVORY may increase the risk of infections. Obtain acomplete blood count (CBC) before initiating treatment. Monitor forinfection during treatment and for 1-2 weeks after discontinuation. Donot start PONVORY in patients with active infection. (5.1)

Bradyarrhythmia and Atrioventricular Condition Delays: PONVORY mayresult in a transient decrease in heart rate; titration is required fortreatment initiation. Check an electrocardiogram (ECG) to assess forpreexisting cardiac condition abnormalities before starting PONVORY.Consider cardiology consultation for conduction abnormalities orconcomitant use with other drugs that decrease heart rate. (5.2, 7.2,7.3)

Respiratory Effects: May cause a decline in pulmonary function. Assesspulmonary function (e.g., spirometry) if clinically indicated. (5.3)

Liver Injury: Discontinue if significant liver injury is confirmed.Obtain liver function tests before initiating PONVORY. (5.4)

Increased Blood Pressure (BP): Monitor BP during treatment. (5.5)

Cutaneous Malignancies: Periodic skin examination is recommended. (5.6)

Fetal Risk: Women of childbearing potential should use effectivecontraception during and for 1 week after stopping PONVORY. (5.7)

Macular Edema: An ophthalmic evaluation is recommended before startingtreatment and if there is any change in vision while taking PONVORY.Diabetes mellitus and uveitis increase the risk. (5.8)

Adverse Reactions

Most common adverse reactions (incidence at least 10%) are upperrespiratory tract infection, hepatic transminase elevation andhypertension. (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals,Inc. at 1400-JANSSEN (1400426-7736) FDA at 1400-FDA-1088 orwww.fda.gov/medwatch.

Drug Interactions

Vaccines: Avoid live attenuated vaccines during and for up to 1-2 weeksafter treatment with PONVORY (7.4)

Strong CYP3A4 and UGT1A1 Inducers: Coadministration with PONVORY is notrecommended (7.5)

Use in Specific Populations

Hepatic Impairment: PONVORY is not recommended in patients with moderateor severe hepatic impairment (Child-Pugh class B and C). (8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Full Prescribing Information: Contents*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Assessments Prior to First Dose of PONVORY

2.2 Recommended Dosage

2.3 First Dose Monitoring in Patients with Certain Preexisting CardiacConditions

2.4 Reinitiation of PONVORY After Treatment Interruption

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Infections

5.2 Bradyarrhythmia and Atrioventricular Conduction Delays

5.3 Respiratory Effects

5.4 Liver Injury

5.5 Increased Blood Pressure

5.8 Cutaneous Malignancies

5.7 Fetal Risk

5.8 Macular Edema

5.9 Posterior Reversible Encephalopathy Syndrome

5.10 Unintended Additive Immunosuppressive Effects From Prior TreatmentWith Immunosuppressive or Immune-Modulating Therapies

5.11 Severe Increase in Disability After Stopping PONVORY

5.12 Immune System Effects After Stopping PONVORY

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies

7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs that may DecreaseHeart Rate

7.3 Beta-Blockers

7.4 Vaccination

7.5 Strong CYP3A4 and UGT1A1 Inducers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

82 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handing

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from full prescribing information arenot listed.

Full Prescribing Information 1. Indications and Usage

PONVORY is indicated for the treatment of relapsing forms of multiplesclerosis (MS), to include clinically isolated syndrome,relapsing-remitting disease, and active secondary progressive disease,in adults.

2. Dosage and Administration

2.1 Assessments Prior to First Dose of PONVORY

Before initiation of treatment with PONVORY, assess the following:

Complete Blood Count

Obtain a recent (i.e., within the last 6 months or after discontinuationof prior MS therapy) complete blood count (CBC), including lymphocytecount [see Warnings and Precautions (5.1)].

Cardiac Evaluation

Obtain an electrocardiogram (ECG) to determine whether preexistingconduction abnormalities are present. In patients with certainpreexisting conditions, advice from a cardiologist should be sought andfirst-dose monitoring is recommended [see Dosage and Administration(2.3) and Warnings and Precautions (5.2)].

Determine whether patients are taking drugs that could slow heart rateor atrioventricular (AV) conduction [see Warnings and Precautions (5.2)]and Drug Interactions (7.2, 7.3)].

Liver Function Tests

Obtain recent (i.e., within the last 6 months) transaminase andbilirubin levels [see Warnings and Precautions [(5.4)].

Ophthalmic Evaluation

Obtain an evaluation of the fundus, including the macula [see Warningsand Precautions (5.8)].

Current or Prior Medications with Immune System Effects

If patients are taking anti-neoplastic, immunosuppressive, orimmune-modulating therapies, or if there is a history of prior use ofthese drugs, consider possible unintended additive immunosuppressiveeffects before initiating treatment with PONVORY [see Warnings andPrecautions (5.1, 5.10) and Drug Interactions (7.1)].

Vaccinations

Test patients for antibodies to varicella zoster virus (VZV) beforeinitiating PONVORY; VZV vaccination of antibody-negative patients isrecommended prior to commencing treatment with PONVORY [see Warnings andPrecautions (5.1)]. If live attenuated vaccine immunizations arerequired, administer at least 1 month prior to initiation of PONVORY.

2.2. Recommended Dosage

Maintenance Dosage

After dose titration is complete (see Treatment Initiation), therecommended maintenance dosage of PONVORY is 20 mg taken orally oncedaily starting on Day 15. Administer PONVORY orally once daily. Swallowthe tablet whole. PONVORY can be taken with or without food.

Treatment Initiation

A starter pack must be used for patients initiating treatment withPONVORY [see How Supplied/Storage and Handling (161)]. Initiate PONVORYtreatment with a 14-day titration; start with one 2 mg tablet orallyonce daily and progress with the titration schedule as shown in Table 19[see Warnings and Precautions (5.2)].

TABLE 19 Dose Titration Regimen Daily Dose Titration Day Days 1 and 2 2mg Days 3 and 4 3 mg Days 5 and 6 4 mg Day 7 5 mg Day 8 6 mg Day 9 7 mgDay 10 8 mg Day 11 9 mg Days 12, 13, and 14 10 mg  Maintenance Day 15and thereafter 20 mg 

If dose titration is interrupted, missed dose instructions must befollowed [see Dosage and Administration (2.4)].

2.3 First Dose Monitoring in Patients with Certain Preexisting CardiacConditions

Because initiation of PONVORY treatment results in a decrease in heartrate (HR). first-dose 4-hour monitoring is recommended for patients withsinus bradycardia [HR less than 55 beats per minute (bpm)], first- orsecond-degree [Mobitz type I] AV block, or a history of myocardialinfarction or heart failure occurring more than 6 months prior totreatment initiation and in stable condition [see Warnings andPrecautions (5.3) and Clinical Pharmacology (12.2)].

First Dose 4-Hour Monitoring

Administer the first dose of PONVORY in a setting where resources toappropriately manage symptomatic bradycardia are available. Monitorpatients for 4 hours after the first dose for signs and symptoms ofbradycardia with a minimum of hourly pulse and blood pressuremeasurements. Obtain an ECG in these patients prior to dosing and at theend of the 4-hour observation period.

Additional Monitoring After 4-Hour Monitoring

If any of the following abnormalities are present after 4 hours (even inthe absence of symptoms). continue monitoring until the abnormalityresolves:

The heart rate 4 hours post-dose is less than 45 bpm

The heart rate 4 hours post-dose is at the lowest value post-dose,suggesting that the maximum pharmacodynamic effect on the heart may nothave occurred The ECG 4 hours post-dose shows new onset second-degree orhigher AV block.

If post-dose symptomatic bradycardia, bradyarrhythmia, or conductionrelated symptoms occur, or if ECG 4 hours post-dose shows new onsetsecond degree or higher AV block or QTc greater than or equal to 500msec, initiate appropriate management, begin continuous ECG monitoring,and continue monitoring until the symptoms have resolved if nopharmacological treatment is required. If pharmacological treatment isrequired, continue monitoring overnight and repeat 4-hour monitoringafter the second dose.

Advice from a cardiologist should be sought to determine the mostappropriate monitoring strategy (which may include overnight monitoring)during treatment initiation, if treatment with PONVORY is considered inpatients:

With some preexisting heart and cerebrovascular conditions [see Warningsand Precautions (5.2)]

With a prolonged QTc interval before dosing or during the 4-hourobservation, or at additional risk for QT prolongation, or on concurrenttherapy with QT prolonging drugs with a known risk of torsades depointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]

Receiving concurrent therapy with drugs that slow heart rate or AVconduction [see Drug Interactions (7.2, 7.3)].

2.4 Reinitiation of PONVORY After Treatment Interruption

Interruption during treatment, especially during titration, is notrecommended; however:

If fewer than 4 consecutive doses are missed:

-   -   during titration: resume treatment with the first missed        titration dose and resume the titration schedule at that dose        and titration day.    -   during maintenance: resume treatment with the maintenance        dosage.

If 4 or more consecutive doses are missed during titration ormaintenance:

-   -   treatment should be reinitiated with Day 1 of the titration        regimen (new starter pack).

If treatment needs to be reinitiated with Day 1 of the titration regimen(new starter pack), complete first-dose monitoring in patients for whomit is recommended [see Dosage and Administration (2.3)].

3. Dosage Forms and Strengths

PONVORY is available as round, biconvex, film-coated tablets for oraluse. PONVORY contains ponesimod in the following dosage strengths (seeTable 20).

TABLE 20 Dosage Form and Strengths for PONVORY Tablet Tablet TabletStrength Color Size Tablet Debossing 2 mg White 5.0 mm “2” on one sideand an arch on the other side. 3 mg Red 5.0 mm “3” on one side and anarch on the other side. 4 mg Purple 5.0 mm “4” on one side and an archon the other side. 5 mg Green 8.6 mm “5” on one side and an arch and an“A” on the other side. 6 mg White 8.6 mm “6” on one side and an arch andan “A” on the other side. 7 mg Red 8.6 mm “7” on one side and an archand an “A” on the other side. 8 mg Purple 8.6 mm “8” on one side and anarch and an “A” on the other side. 9 mg Brown 8.6 mm “9” on one side andan arch and an “A” on the other side. 10 mg  Orange 8.6 mm “10” on oneside and an arch and an “A” on the other side. 20 mg  Yellow 8.6 mm “20”on one side and an arch and an “A” on the other side.

4. Contraindications

PONVORY is contraindicated in patients who:

In the last 6 months, have experienced myocardial infarction, unstableangina, stroke, transient ischemic attack (TLA), decompensated heartfailure requiring hospitalization, or Class III or IV heart failure [seeWarnings and Precautions (5.2)]

Have presence of Mobitz type II second-degree. third-degreeatrioventricular (AV) block, or sick sinus syndrome, or sino-atrialblock, unless patient has a functioning pacemaker [see Warnings andPrecautions (5.2)].

5. Warnings and Precautions

5.1 Infections

Risk of Infections

PONVORY causes a dose-dependent reduction in peripheral lymphocyte countto 30-40% of baseline values because of reversible sequestration oflymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)].PONVORY may therefore increase the susceptibility to infections.Life-threatening and rare fatal infections have been reported inassociation with other sphingosine 1-phosphate (SIP) receptormodulators.

In Study 1 [see Clinical Studies (14)]. the overall rate of infectionswas comparable between the PONVORY-treated patients and those receivingteriflunomide 14 mg (54.2% vs 52.1%, respectively). PONVORY increasedthe risk of upper respiratory tract infections. Serious or severeinfections occurred in 1.6% of PONVORY-treated patients compared to 0.9%of patients receiving teriflunomide 14 mg.

Before initiating treatment with PONVORY, results from a recent (i.e.,within 6 months or after discontinuation of prior therapy) completeblood count including lymphocyte count should be reviewed.

Initiation of treatment with PONVORY should be delayed in patients withactive infection until resolution. Lymphocyte counts returned to thenormal range in 90% of patients within 1 week of stopping therapy inmodeling studies [see Clinical Pharmacology (12.2)]. In Study 1,peripheral lymphocyte counts returned to normal range within 2 weeksafter discontinuation of PONVORY, which was the first timepointevaluated. Because residual pharmacodynamic effects, such as loweringeffects on peripheral lymphocyte count, may persist for 1 to 2 weeksafter discontinuation of PONVORY, vigilance for infection should becontinued for 1 to 2 weeks after PONVORY is discontinued [see Warningsand Precautions (5.12)].

In Study 1, the proportion of patients who experienced lymphocyte countsless than 0.2×10⁹/L was 3.2%. Effective diagnostic and therapeuticstrategies should be employed in patients with symptoms of infectionwhile on therapy. Consider interruption of treatment with PONVORY if apatient develops a serious infection.

Herpes Viral Infections

Cases of herpes viral infection have been reported in the developmentprogram of PONVORY; herpes simplex encephalitis and varicella zostermeningitis have been reported with other S1P receptor modulators.

In Study 1, the rate of herpetic infections was 4.8% for bothPONVORY-treated patients and those receiving teriflunomide 14 mg.Patients without a healthcare professional confirmed history ofvaricella (chickenpox) or without documentation of a full course ofvaccination against VZV should be tested for antibodies to VZV beforeinitiating PONVORY (see Vaccinations).

Cryptococcal Infections

Cases of fatal cryptococcal meningitis (CM) and disseminatedcryptococcal infections have been reported with other SIP receptormodulators. Physicians should be vigilant for clinical symptoms or signsof CM. Patients with symptoms or signs consistent with a cryptococcalinfection should undergo prompt diagnostic evaluation and treatment.PONVORY treatment should be suspended until a cryptococcal infection hasbeen excluded. If CM is diagnosed, appropriate treatment should beinitiated.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunisticviral infection of the brain caused by the JC virus (JCV) that typicallyonly occurs in patients who are immunocompromised, and that usuallyleads to death or severe disability. Typical symptoms associated withPML are diverse, progress over days to weeks. and include progressiveweakness on one side of the body or clumsiness of limbs, disturbance ofvision, and changes in thinking, memory, and orientation leading toconfusion and personality changes.

PML has been reported in patients treated with a S1P receptor modulatorand other multiple sclerosis (MS) therapies and has been associated withsome risk factors (e.g., immunocompromised patients, polytherapy withimmunosuppressants). Physicians should be vigilant for clinical symptomsor magnetic resonance imaging (MRI) findings that may be suggestive ofPML. MRI findings may be apparent before clinical signs or symptoms. IfPML is suspected, treatment with PONVORY should be suspended until PMLhas been excluded. If PML is confirmed, treatment with PONVORY should bediscontinued.

Prior and Concomitant Treatment with Anti-neoplastic. Immune-Modulating,or Immunosuppressive Therapies

Anti-neoplastic, immune-modulating, or immunosuppressive therapies(including corticosteroids) should be coadministered with cautionbecause of the risk of additive immune system effects [see DrugInteractions (7.1)].

Vaccinations

Patients without a healthcare professional confirmed history ofchickenpox or without documentation of a full course of vaccinationagainst VZV should be tested for antibodies to VZV before initiatingPONVORY treatment. A full course of vaccination for antibody-negativepatients with varicella vaccine is recommended prior to commencingtreatment with POVORY, following which initiation of treatment withPONVORY should be postponed for 4 weeks to allow the full effect ofvaccination to occur.

No clinical data are available on the efficacy and safety ofvaccinations in patients taking PONVORY. Vaccinations may be lesseffective if administered during PONVORY treatment.

If live attenuated vaccine immunizations are required, administer atleast 1 month prior to initiation of PONVORY. Avoid the use of liveattenuated vaccines during and for 1 to 2 weeks after treatment withPONVORY.

5.2 Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of PONVORY treatment results in a transient decrease inheart rate and atrioventricular (AV) conduction delays, an up-titrationscheme must be used to reach the maintenance dosage of PONVORY (20 mg)[see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

Study 1 did not include patients who had:

A resting heart rate (HR) less than 50 beats per minute (bpm) onbaseline electrocardiogram

Myocardial infarction or unstable ischemic heart disease in the last 6months

Cardiac failure (New York Heart Association class III-IV) or presence ofany severe cardiac disease

Cardiac conduction or rhythm disorders (including sino-atrial heartblock, symptomatic bradycardia, atrial flutter or atrial fibrillation,ventricular arrhythmia, cardiac arrest) either in history or observed atscreening

Mobitz Type II second degree AV block or higher-grade AV block observedat screening

QTcF interval greater than 470 ms (females) and greater than 450 ms(males) observed at screening

History of syncope associated with cardiac disorders

Uncontrolled systemic arterial hypertension Reduction in Heart Rate.

Reduction in Heart Rate

Initiation of PONVORY may result in a transient decrease in HR. In Study1, bradycardia at treatment initiation and sinus bradycardia on ECG(defined as HR less than 50 bpm) occurred in 5.8% of PONVORY-treatedpatients compared to 1.6% of patients receiving teriflunomide 14 mg.After the first titration dose of PONVORY, the decrease in heart ratetypically begins within an hour and reaches its nadir within 2-4 hours.The heart rate typically recovers to baseline levels 4-5 hours afteradministration. The mean decrease in heart rate on Day 1 of dosing was 6bpm. With up-titration after Day 1, the post-dose decrease in heart rateis less pronounced. Bradycardia resolved in all patients in Study 1without intervention and did not require discontinuation of PONVORYtreatment. On Day 1, 3 patients treated with PONVORY had asymptomaticpost-dose HR below or equal to 40 bpm; all 3 patients had baseline HRsbelow 55 bpm.

Atrioventricular Conduction Delays

Initiation of PONVORY treatment has been associated with transientatrioventricular conduction delays that follow a similar temporalpattern as the observed decrease in heart rate during dose titration. InStudy 1, the AV conduction delays manifested as first-degree AV block(prolonged PR interval on ECG). which occurred in 3.4% ofPONVORY-treated patients and in 1.2% of patients receiving teriflunomide14 mg. The conduction abnormalities typically were transient,asymptomatic, resolved within 24 hours, resolved without intervention,and did not require discontinuation of PONVORY treatment. In Study 1,second- and third-degree AV blocks were not reported in patients treatedwith PONVORY.

If treatment with PONVORY is considered, advice from a cardiologistshould be sought for individuals:

With significant QT prolongation (QTc greater than 500 msec)

With atrial flutter fibrillation or arrhythmia treated with Class Ia orClass III anti-arrhythmic drugs [see Drug Interactions (7.2)]

With unstable ischemic heart disease, cardiac decompensated failureoccurring more than 6 months prior to treatment initiation history ofcardiac arrest, cerebrovascular disease (TIA, stroke occurring more than6 months prior to treatment initiation), or uncontrolled hypertension

With a history of Mobitz Type II second degree AV block or higher-gradeAV block, sick-sinus syndrome, or sino-atrial heart block [seeContraindications (4)].

Treatment Initiation Recommendations

Obtain an ECG in all patients to determine whether preexistingconduction abnormalities are present.

In all patients, a dose titration is recommended for initiation ofPONVORY treatment to help reduce cardiac effects [see Dosage andAdministration (2.2)].

In patients with sinus bradycardia, first- or second-degree [Mobitz typeI] AV block, or a history of myocardial infarction or heart failure withonset more than 6 months prior to initiation first-dose monitoring isrecommended [see Dosage and Administration (2.1, 2.3)].

PONVORY is not recommended in patients with a history of cardiac arrest,cerebrovascular disease (e.g., TIA, stroke occurring more than 6 monthsprior to treatment initiation), uncontrolled hypertension, or severeuntreated sleep apnea, since significant bradycardia may be poorlytolerated in these patients. If treatment is considered, advice from acardiologist should be sought prior to initiation of treatment in orderto determine the most appropriate monitoring strategy.

Use of PONVORY in patients with a history of recurrent syncope orsymptomatic bradycardia should be based on an overall benefit-riskassessment. If treatment is considered, advice from a cardiologistshould be sought prior to initiation of treatment in order to determinethe most appropriate monitoring.

Experience with PONVORY is limited in patients receiving concurrenttherapy with drugs that decrease heart rate (e.g., beta-blockers,non-dihydropyridine calcium channel blockers—diltiazem and verapamil,and other drugs that may decrease heart rate such as digoxin).Concomitant use of these drugs during PONVORY initiation may beassociated with severe bradycardia and heart block. If treatment isconsidered, advice from a cardiologist should be sought prior toinitiation of treatment in order to determine the most appropriatemonitoring.

For patients receiving a stable dose of a beta-blocker, the restingheart rate should be considered before introducing PONVORY treatment. Ifthe resting heart rate is greater than 55 bpm under chronic beta-blockertreatment, PONVORY can be introduced. If resting heart rate is less thanor equal to 55 bpm, beta-blocker treatment should be interrupted untilthe baseline heart rate is greater than 55 bpm. Treatment with PONVORYcan then be initiated and treatment with a beta-blocker can bereinitiated after PONVORY has been up-titrated to the target maintenancedosage [see Drug Interactions (7.3)].

For patients taking other drugs that decrease heart rate, treatment withPONVORY should generally not be initiated without consultation from acardiologist because of the potential additive effect on heart rate [seeDosage and Administration (2.3) and Drug Interactions (7.2)].

Missed Dose During Treatment Initiation or Maintenance Treatment

If 4 or more consecutive daily doses are missed during treatmentinitiation or maintenance treatment, reinitiate Day 1 of the dosetitration (new starter pack) and follow first-dose monitoringrecommendations [see Dosage and Administration (2.4)].

5.3 Respiratory Effects

Dose-dependent reductions in forced expiratory volume over 1 second(FEV₁) and reductions in diffusion lung capacity for carbon monoxide(DL_(CO)) were observed in PONVORY-treated patients mostly occurring inthe first month after treatment initiation. In Study 1, the reductionfrom baseline in percent predicted FEV₁ at 2 years was 8.3% inPONVORY-treated patients compared to 4.4% in patients receivingteriflunomide 14 mg. In Study 1, 7 patients discontinued PONVORY becauseof pulmonary adverse events. There is insufficient information todetermine the reversibility of the decrease in FEV₁ or FVC aftertreatment discontinuation. PONVORY should be used with caution inpatients with severe respiratory disease (i.e., pulmonary fibrosis,asthma, and chronic obstructive pulmonary disease). Spirometricevaluation of respiratory function should be performed during therapywith PONVORY if clinically indicated.

5.4 Liver Injury

Elevations of transaminases may occur in PONVORY-treated patients.

Obtain transaminase and bilirubin levels, if not recently available(i.e., within last 6 months) before initiation of PONVORY.

In Study 1, elevations of ALT to 5-fold the upper limit of normal (ULN)or greater occurred in 4.6% of patients treated with PONVORY compared to2.5% of patients who received teriflunomide 14 mg. Elevation of ALT to3-fold the ULN or greater occurred in 17.3% of patients treated withPONVORY and 8.3% of patients treated with teriflunomide 14 mg. Themedian time to an elevation of 3-fold the ULN was 3 months. The majority(89%) of patients with ALT increases 3-fold or greater the ULN continuedtreatment with PONVORY with values returning to less than three timesthe ULN within approximately 2-4 weeks.

In Study 1, the discontinuation rate because of elevations in hepaticenzymes was 2.3% of patients treated with PONVORY and 1.9% of patientswho received teriflunomide 14 mg.

Patients who develop symptoms suggestive of hepatic dysfunction, such asunexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rashwith eosinophilia, or jaundice and/or dark urine during treatment,should have hepatic enzymes checked. PONVORY should be discontinued ifsignificant liver injury is confirmed.

No dosage adjustment is necessary in patients with mild hepaticimpairment (Child-Pugh class A). PONVORY is not recommended in patientswith moderate or severe hepatic impairment (Child-Pugh class B and C,respectively) [see Use in Specific Populations (8.6) and ClinicalPharmacology (12.3)].

5.5 Increased Blood Pressure

In Study 1, PONVORY-treated patients had an average increase of 2.9 mmHg in systolic blood pressure and 2.8 mm Hg in diastolic blood pressurecompared to 2.8 mm Hg and 3.1 mm Hg in patients receiving teriflunomide14 mg, respectively. An increase in blood pressure with PONVORY wasfirst detected after approximately 1 month of treatment initiation andpersisted with continued treatment. Hypertensive events were reported asan adverse reaction in 10.1% of PONVORY-treated patients and in 9.0% ofpatients receiving teriflunomide 14 mg. One patient treated with PONVORYexperienced a hypertensive crisis but had evidence of longstandinghypertensive heart disease. Blood pressure should be monitored duringtreatment with PONVORY and managed appropriately.

5.6 Cutaneous Malignancies

Cases of basal cell carcinoma and other skin malignancies have beenreported in patients treated with SIP receptor modulators, includingPONVORY. In Study 1, the incidence of basal cell carcinoma was 0.4% inPONVORY-treated patients compared to 0.2% in patients receivingteriflunomide 14 mg. Cases of other cutaneous malignancies, includingmelanoma and squamous cell carcinoma, have also been reported inpatients treated with PONVORY and in patients treated with other SIPmodulators.

Periodic skin examination is recommended for all patients, particularlythose with risk factors for skin cancer. Providers and patients areadvised to monitor for suspicious skin lesions. If a suspicious skinlesion is observed, it should be promptly evaluated. As usual forpatients with increased risk for skin cancer, exposure to sunlight andultraviolet light should be limited by wearing protective clothing andusing a sunscreen with a high protection factor. Concomitantphototherapy with UV-B radiation or PUVA-photochemotherapy is notrecommended in patients taking PONVORY.

5.7 Fetal Risk

Based on animal studies, PONVORY may cause fetal harm [see Use inSpecific Populations 8.1, 8.3)]. Because it takes approximately 1 weekto eliminate PONVORY from the body, women of childbearing potentialshould use effective contraception to avoid pregnancy during and for 1week after stopping PONVORY treatment.

5.8 Macular Edema

S1P receptor modulators, including PONVORY, have been associated with anincreased risk of macular edema. In Study 1, macular edema was reportedin 1.1% of PONVORY-treated patients compared to none of the patientsreceiving teriflunomide 14 mg.

An ophthalmic evaluation of the fundus, including the macula, isrecommended in all patients before starting treatment and again at anytime if a patient reports any change in vision while on PONVORY therapy.

Continuation of PONVORY therapy in patients with macular edema has notbeen evaluated. A decision on whether PONVORY should be discontinuedshould take into account the potential benefits and risks for theindividual patient.

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus

Patients with a history of uveitis and patients with diabetes mellitusare at increased risk of macular edema during therapy with S1P receptormodulators, including PONVORY. Therefore, these patients should haveregular follow-up examinations of the fundus, including the macula,during treatment with PONVORY.

5.9 Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) havebeen reported in patients receiving a sphingosine 1-phosphate (SIP)receptor modulator. Such events have not been reported forPONVORY-treated patients in the development program. However, should aPONVORY-treated patient develop any unexpected neurological orpsychiatric symptoms/signs (e.g., cognitive deficits, behavioralchanges, cortical visual disturbances, or any other neurologicalcortical symptoms/signs), any symptom/sign suggestive of an increase ofintracranial pressure, or accelerated neurological deterioration, thephysician should promptly schedule a complete physical and neurologicalexamination and should consider an MRI. Symptoms of PRES are usuallyreversible but may evolve into ischemic stroke or cerebral hemorrhage.Delay in diagnosis and treatment may lead to permanent neurologicalsequelae. If PRES is suspected, PONVORY should be discontinued.

5.10 Unintended Additive Immunosuppressive Effects From Prior TreatmentWith Immunosuppressive or Immune-Modulating Therapies

When switching from drugs with prolonged immune effects, the half-lifeand mode of action of these drugs must be considered in order to avoidunintended additive effects on the immune system while at the same timeminimizing risk of disease reactivation, when initiating PONVORY.

Initiating treatment with PONVORY after treatment with alemtuzumab isnot recommended.

5.11 Severe Increase in Disability After Stopping PONVORY

Severe exacerbation of disease, including disease rebound. has beenrarely reported after discontinuation of a S1P receptor modulator. Thepossibility of severe exacerbation of disease should be considered afterstopping PONVORY treatment. Patients should be observed for a severeincrease in disability upon PONVORY discontinuation and appropriatetreatment should be instituted, as required.

5.12 Immune System Effects After Stopping PONVORY

After stopping PONVORY therapy, ponesimod remains in the blood for up to1 week. Starting other therapies during this interval will result inconcomitant exposure to ponesimod. Lymphocyte counts returned to thenormal range in 90% of patients within 1 week of stopping PONVORYtherapy in modeling studies [see Clinical Pharmacology (12.2)]. However,residual pharmacodynamics effects, such as lowering effects onperipheral lymphocyte count, may persist for 1 to 2 weeks after the lastdose. Use of immune-suppressants within this period may lead to anadditive effect on the immune system, and therefore caution should beapplied 1 to 2 weeks after the last dose of PONVORY [see DrugInteractions (7.1)].

6. Adverse Reactions

The following serious adverse reactions are described elsewhere inlabeling: Infections [see Warnings and Precautions (5.1)]

Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings andPrecautions (5.2)]

Respiratory Effects [see Warnings and Precautions (5.3)]

Liver Injury [see Warnings and Precautions (5.4)]

Increased Blood Pressure [see Warnings and Precautions (5.5)]

Cutaneous Malignancies [see Warnings and Precautions (5.6)]

Fetal Risk [see Warnings and Precautions (5.7)]

Macular Edema [see Warnings and Precautions (5.8)]

Posterior Reversible Encephalopathy Syndrome [see Warnings andPrecautions (5.9)]

Unintended Additive Immunosuppressive Effects From Prior Treatment WithImmunosuppressive or Immune-Modulating Therapies [see Warnings andPrecautions (5.10)]

Severe Increase in Disability After Stopping PONVORY [see Warnings andPrecautions (5.11)]

Immune System Effects After Stopping PONVORY [see Warnings andPrecautions (5.12)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of a drug cannotbe directly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in practice.

A total of 1438 MS patients have received PONVORY at doses of at least 2mg daily. These patients were included in Study 1 (2-yearactive-controlled versus teriflunomide 14 mg) [see Clinical Studies(14)] and in a Phase 2 (6-month placebo-controlled) study in patientswith MS and the uncontrolled extension studies.

In Study 1, 82% of PONVORY-treated patients completed 2 years of studytreatment, compared to 82.2% of patients receiving teriflunomide 14 mg.Adverse events led to discontinuation of treatment in 8.7% ofPONVORY-treated patients. compared to 6% of patients receivingteriflunomide 14 mg. The most common adverse reactions (incidence atleast 10%) in PONVORY-treated patients in Study 1 were upper respiratorytract infection, hepatic transaminase elevation, and hypertension. Table21 lists adverse reactions that occurred in at least 2% ofPONVORY-treated patients and at a higher rate than in patients receivingteriflunomide 14 mg.

TABLE 21 Adverse Reactions Reported in Study 1 Occurring in at Least 2%of PONVORY-Treated Patients and at a Higher Rate Than in PatientsReceiving Teriflunomide 14 mg Teriflunomide PONVORY 14 mg N = 565 N =566 Adverse Reaction (%) (%) Upper respiratory infection ^(a) 37 34Hepatic transaminase elevation ^(b) 23 12 Hypertension ^(c) 10 9 Urinarytract infection 6 5 Dyspnea 5 1 Dizziness 5 3 Cough 4 2 Pain inextremity 4 3 Somnolence 3 2 Pyrexia 2 1 C-reactive protein increased 21 Hypercholesterolemia 2 1 Vertigo 2 1 ^(a) Includes the followingterms: nasopharyngitis, upper respiratory tract infection, pharyngitis,respiratory tract infection, bronchitis, respiratory tract infectionviral, viral upper respiratory tract infection, tracheitis, andlaryngitis. ^(b) Includes the following terms: alanine aminotransferaseincreased, aspartate aminotransferase increased, hepatic enzymeincreased, and transaminases increased ^(c) Includes the followingterms: hypertension, hypertensive crisis, blood pressure increased,blood pressure systolic increased, and blood pressure diastolicincreased.

In Study 1, the following adverse reactions occurred in less than 2% ofPONVORY-treated patients, but at a rate at least 1% higher than inpatients receiving teriflunomide 14 mg: viral infection, herpes zoster,hyperkalemia, lymphopenia [see Warnings and Precautions (5.1), andmacular edema [see Warnings and Precautions (5.8)].

Adverse reactions in patients treated with PONVORY in an additional6-month placebo-controlled study were generally similar to those inStudy 1. The following additional adverse reactions occurred in at least2% of PONVORY 20 mg-treated patients and at a higher rate than inpatients receiving placebo (but did not meet the reporting rate criteriafor inclusion in Study 1): rhinitis, fatigue, chest discomfort,peripheral edema, joint swelling, blood cholesterol increased, migraine,insomnia, depression, dyspepsia, dry mouth, bradycardia, back pain, andsinusitis.

Additionally, in uncontrolled extension trials, the adverse reaction ofpneumonia was reported.

Seizures

In Study 1, cases of seizures were reported in 1.4% of PONVORY-treatedpatients, compared to 0.2% in patients receiving teriflunomide 14 mg. Itis not known whether these events were related to the effects of MS, toPONVORY, or to a combination of both.

Respiratory Effects

In Study 1, dose-dependent reductions in forced expiratory volume over 1second (FEV₁) were observed in patients treated with PONVORY [seeWarnings and Precautions (5.3)].

Malignancies

In Study 1, two cases of basal cell carcinoma (0.4%) were reported inPONVORY-treated patients, compared to one case of basal cell carcinoma(0.2%) in patients receiving teriflunomide 14 mg, and a case ofmalignant melanoma was reported in a PONVORY-treated patient. Anincreased risk of cutaneous malignancies has been reported inassociation with other SIP receptor modulators, including PONVORY [seeWarnings and Precautions (5.6)].

7. Drug Interactions

7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies

PONVORY has not been studied in combination with anti-neoplastic,immune-modulating, or immunosuppressive therapies. Caution should beused during concomitant administration because of the risk of additiveimmune effects during such therapy and in the weeks followingadministration [see Warnings and Precautions (5.1)].

When switching from drugs with prolonged immune effects, the half-lifeand mode of action of these drugs must be considered in order to avoidunintended additive effects on the immune system [see Warnings andPrecautions (5.10)].

Because of the characteristics and duration of alemtuzumab immunesuppressive effects, initiating treatment with PONVORY after alemtuzumabis not recommended.

PONVORY can generally be started immediately after discontinuation ofbeta interferon or glatiramer acetate.

7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs that may DecreaseHeart Rate

PONVORY has not been studied in patients taking QT prolonging drugs.

Class Ia (e.g., quinidine, procainamide) and Class III (e.g.,amiodarone, sotalol) anti-arrhythmic drugs have been associated withcases of Torsades de Pointes in patients with bradycardia. If treatmentwith PONVORY is considered. advice from a cardiologist should be sought.

Because of the potential additive effects on heart rate, treatment withPONVORY should generally not be initiated in patients who areconcurrently treated with QT prolonging drugs with known arrhythmogenicproperties, heart rate lowering calcium channel blockers (e.g.,verapamil, diltiazem), or other drugs that may decrease heart rate(e.g., digoxin) [see Warnings and Precautions (5.2) and DrugInteractions (7.3)]. If treatment with PONVORY is considered, advicefrom a cardiologist should be sought.

7.3 Beta-Blockers

Caution should be applied when PONVORY is initiated in patientsreceiving treatment with a beta-blocker because of the additive effectson lowering heart rate; temporary interruption of the beta-blockertreatment may be needed prior to initiation of PONVORY [see Warnings andPrecautions (5.2)]. Beta-blocker treatment can be initiated in patientsreceiving stable doses of PONVORY.

7.4 Vaccination

During, and for up to 1 to 2 weeks after discontinuation of, treatmentwith PONVORY, vaccinations may be less effective. The use of liveattenuated vaccines may carry the risk of infection and should thereforebe avoided during PONVORY treatment and for 1 to 2 weeks afterdiscontinuation of treatment with PONVORY [see Warnings and Precautions(5.1)].

7.5 Strong CYP3A4 and UGT1A1 Inducers

In vitro assessments and limited clinical data indicated thatconcomitant use of strong CYP3A4 and UGT1A1 inducers (e.g., rifampin,phenytoin, carbamazepine) may decrease the systemic exposure ofponesimod. It is unclear whether this decrease in ponesimod systemicexposure would be considered of clinical relevance. Coadministration ofPONVORY with strong CYP3A4 and UGT1A1 inducers is not recommended.

8. Use in Specific Populations

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of PONVORY in pregnantwomen. In animal studies, administration of ponesimod during pregnancyproduced adverse effects on development, including embryo lethality andfetal malformations, in the absence of maternal toxicity. In rats andrabbits, visceral and skeletal malformations occurred at clinicallyrelevant maternal ponesimod exposures (see Data). The receptor affectedby ponesimod (sphingosine-l-phosphate receptor 1) has been demonstratedto have an important role in embryogenesis, including vascular andneural development.

In the US general population, the estimated background risk of majorbirth defects and miscarriage in clinically recognized pregnancies is2/-4% and 15%-20%, respectively. The background risk of major birthdefects and miscarriage for the indicated population is unknown.

Data

Animal Data

When ponesimod (0, 1, 10, or 40 mg/kg/day) was orally administered topregnant rats during the period of organogenesis, increased incidencesof fetal malformations primarily involving the limbs (syndactyly andectrodactyly) and cardiovascular system (including ventricular septaldefects) were observed at all but the lowest dose tested. A highincidence of embryofetal death was observed at the highest dose tested.Maternal toxicity was not observed, indicating a selective effect on thefetus. Plasma exposure (AUC) at the no-effect dose (1 mg/kg/day) foradverse effects on embryofetal development in rats was lower than thatin humans at the recommended human dose (RHD) of 20 mg/day.

When ponesimod (0, 0.25, 1, or 4 mg/kg/day) was orally administered topregnant rabbits during the period of organogenesis, an increase inpost-implantation loss and fetal variations (visceral and skeletal) werenoted at the highest dose tested. No maternal toxicity was observed.Plasma exposure at the no-effect dose (1 mg/kg/day) for adverse effectson embryofetal development in rabbits was lower than that in humans atthe RHD. In a dose-range finding study in pregnant rabbits. oraladministration of ponesimod (0, 6, 20, or 60 mg/kg/day) duringorganogenesis, an increase in embryofetal death and fetal limbmalformation (brachydactyly) were observed at the lowest dose tested; atthe higher doses, there were no live fetuses.

When ponesimod (5, 10, or 20 mg/kg) was orally administered to femalerats throughout pregnancy and lactation, the offspring exhibiteddecreased survival, reduced body weight gain, and reduced fertility andreproductive performance (increases in pre- and post-implantation loss)at the highest dose tested, neurobehavioral impairment (increasedlocomotor activity) at the mid and high doses, and delayed sexualmaturation at all doses tested. A no-effect dose for adverse effects onpre- and postnatal development in rats was not identified. Plasmaexposure (AUC) in dams at the lowest dose tested was less than that inhumans at the RHD.

8.2 Lactation

Risk Summary

There are no data on the presence of PONVORY in human milk, the effectson the breastfed infant, or the effects of the drug on milk production.When ponesimod was orally administered to female rats during pregnancyand lactation, ponesimod was detected in the plasma of the offspring,suggesting excretion of ponesimod in milk.

The developmental and health benefits of breastfeeding should beconsidered along with the mother's clinical need for PONVORY and anypotential adverse effects on the breastfed infant from PONVORY or fromthe underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Before initiation of PONVORY treatment, women of childbearing potentialshould be counseled on the potential for a serious risk to the fetus andthe need for effective contraception during treatment with PONVORY [seeUse in Specific Populations (8.1)]. Since it takes approximately oneweek to eliminate ponesimod from the body after stopping treatment, thepotential risk to the fetus may persist, and women should use effectivecontraception during this period [see Warnings and Precautions (5.7)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not beenestablished.

Juvenile Animal Toxicity Data

Oral administration of ponesimod (0, 1, 10, 30, or 100 mg/kg/day) toyoung rats from postnatal day 28 to 91 resulted in lung histopathology(alveolar histiocytosis/edema) and decreased immune function (T-celldependent antibody response) at the two highest doses tested. Decreasedgrowth (body weight gain and/or long bone length) was observed at allbut the low dose, and neurobehavioral impairment (increased locomotoractivity) was observed at the highest dose tested. Decreased lymphocytecount and neurobehavioral impairment persisted at the end of a 4-weekrecovery period.

8.5 Geriatric Use

Clinical studies of PONVORY did not include patients 65 years of age andover to determine whether they respond differently from youngersubjects. Use of PONVORY in elderly patients should be cautious,reflecting the greater frequency of decreased hepatic, renal, or cardiacfunction, and of concomitant disease or other drug therapy [see ClinicalPharmacology (12.3)].

8.6 Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepaticimpairment (Child-Pugh class A) [see Clinical Pharmacology (12.3)].

PONVORY is not recommended in patients with moderate or severe hepaticimpairment (Child-Pugh class B and C, respectively), as the risk ofadverse reactions may be greater [see Clinical Pharmacology (12.3)].

9. Overdosage

Symptoms and Signs

In patients with overdosage of PONVORY, especially uponinitiation/re-initiation of treatment, it is important to observe forsigns and symptoms of bradycardia as well as AV conduction blocks, whichmay include overnight monitoring. Regular measurements of pulse rate andblood pressure are required, and ECGs should be performed [see Warningsand Precautions (5.2, 5.5) and Clinical Pharmacology (12.2)].

Treatment

There is no specific antidote to ponesimod. Neither dialysis nor plasmaexchange would result in meaningful removal of ponesimod from the body.The decrease in heart rate induced by PONVORY can be reversed byatropine.

In the event of overdose, PONVORY should be discontinued, and generalsupportive treatment given until clinical toxicity has been diminishedor resolved. It is advisable to contact a poison control center toobtain the latest recommendations for the management of an overdose.

10. Description

PONVORY (ponesimod) is a sphingosine 1-phosphate receptor modulator.

The chemical name for ponesimod is(2Z,5Z)-5-[3-chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene]-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one.It has one chiral center with absolute configuration of (R). Itsmolecular formula is C₂₃H₃₅ClN₂O₄S and its molecular weight is 460.97g/mol. Ponesimod has the following structural formula:

Ponesimod is a white to light yellowish powder that is practicallyinsoluble or insoluble in water.

PONVORY (ponesimod) is provided as 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8mg, 9 mg, 10 mg, and 20 mg film-coated tablets for oral administration.

Each tablet contains the following inactive ingredients: croscarmellosesodium. lactose monohydrate, magnesium stearate, microcrystallinecellulose. povidone K30. silica colloidal anhydrous. and sodium laurylsulfate.

Each tablet coating contains ferrosoferric oxide (included in 4 mg, 5mg, 8 mg, and 9 mg film-coated tablets), hydroxypropyl methylcellulose2910, iron oxide red (included in 3 mg, 4 mg, 7 mg, 8 mg, 9 mg, and 10mg film-coated tablets), iron oxide yellow (included in 3 mg, 5 mg, 7mg, 9 mg, 10 mg, and 20 mg film-coated tablets), lactose monohydrate,polyethylene glycol 3350, titanium dioxide, and triacetin.

11. Clinical Pharmacology

11.1 Mechanism of Action

Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator thatbinds with high affinity to S1P receptor 1.

Ponesimod blocks the capacity of lymphocytes to egress from lymph nodes,reducing the number of lymphocytes in peripheral blood. The mechanism bywhich ponesimod exerts therapeutic effects in multiple sclerosis isunknown, but may involve reduction of lymphocyte migration into thecentral nervous system.

11.2 Pharmacodynamics

Immune System

In healthy volunteers, PONVORY induces a dose-dependent reduction of theperipheral blood lymphocyte count from a single dose of 5 mg onwards,with the greatest reduction observed 6 hours post-dose, caused byreversible sequestration of lymphocytes in lymphoid tissues. After 7daily doses of 20 mg, the greatest decrease in absolute mean lymphocytecount was to 26% of baseline (650 cells/μL), observed 6 hours afteradministration. Peripheral blood B cells [CD19+] and T cells [CD3+],T-helper [CD3+CD4+], and T-cytotoxic [CD3+CD8+] cell subsets are allaffected, while NK cells are not. T-helper cells were more sensitive tothe effects of ponesimod than T-cytotoxic cells.

PK/PD modeling indicates lymphocyte counts returned to the normal rangein greater than 90% of healthy subjects within 1 to 2 weeks of stoppingtherapy. In Study 1, peripheral lymphocyte counts returned to the normalrange within 2 weeks after discontinuation of PONVORY.

Heart Rate and Rhythm

PONVORY causes a transient dose-dependent reduction in heart rate (HR)and AV conduction delays upon treatment initiation [see Warnings andPrecautions (5.2)]. The heart rate decreases plateaued at doses greaterthan or equal to 40 mg [2 times the recommended maintenance dosage], andbradyarrhythmic events (AV blocks) were detected at a higher incidenceunder PONVORY treatment, compared to placebo. This effect starts withinthe first hour of dosing and is maximal at 2-4 hours post-dose. HRgenerally returns to pre-dose values by 4-5 hours post-dose on Day 1,and the effect diminishes with repeated administration. indicatingtolerance.

The decrease in heart rate induced by ponesimod can be reversed byatropine.

Beta-Blockers

The negative chronotropic effect of coadministration of PONVORY andpropranolol was evaluated in a dedicated pharmacodynamics safety study.The addition of PONVORY to propranolol at steady state has an additiveeffect on HR effect [see Drug Interactions (7.3)].

Cardiac Electrophysiology

In a thorough QT study, daily administration of ponesimod doses of 40 mgand 100 mg (respectively 2- and 5-fold the recommended maintenance dose)until steady-state conditions were achieved resulted in prolongation ofFridericia-corrected QT (QTcF) intervals, with the maximum mean (upperbound of 90% two-sided confidence interval) at 11.8 ms (40 mg) and 16.2ms (100 mg). No subject had absolute QTcF greater than 480 ms or ΔQTcFgreater than 90 ms for ponesimod treatment.

Pulmonary Function

Dose-dependent reductions in FEV₁ and FVC were observed inPONVORY-treated subjects, and were greater than in subjects takingplacebo [see Warnings and Precautions (5.3)]. These effects can bereversed with administration of a short acting beta2 agonist.

11.3 Pharmacokinetics

Following ponesimod oral dosing, C_(max) and AUC increased approximatelydose-proportionally in the dose-range studied (1-75 mg). Steady-statelevels are approximately 2.0- to 2.6-fold greater than with a singledose, and are achieved following 3 days of administration of themaintenance dose of ponesimod.

The pharmacokinetics of ponesimod are similar in healthy subjects andpatients with multiple sclerosis, with 25% inter-subject variabilityacross studies.

Absorption

The time to reach maximum plasma concentration of ponesimod is 2-4 hourspost-dose. The absolute oral bioavailability of a 10 mg dose is 84%.

Food Effect

Food does not have a clinically relevant effect on ponesimodpharmacokinetics; therefore, PONVORY may be taken with or without food.

Distribution

Following IV administration in healthy subjects, the steady-state volumeof distribution of ponesimod is 160 L.

Ponesimod is highly bound to plasma proteins (>99%) and is mainly(78.5%) distributed in the plasma fraction of whole blood. Animalstudies show that ponesimod readily crosses the blood-brain-barrier.

Metabolism

Ponesimod is extensively metabolized prior to excretion in humans,though unchanged ponesimod was the main circulating component in plasma.Two inactive circulating metabolites, M12 and M13, have also beenidentified in human plasma. M13 and M12 are respectively about 20% and6% of total drug-related exposure. Both metabolites are inactive at S1Preceptors at concentrations achieved with recommended doses ofponesimod.

Experiments with human liver preparations indicate that metabolism ofponesimod to M13 occurs primarily through a combination ofnon-Cytochrome P450 (CYP450) enzymatic activities. Multiple CYP450(CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12) and non-CYP450 enzymescatalyze the oxidation of ponesimod to M12. Ponesimod also undergoesdirect glucuronidation (mainly UGT1A1 and UGT2B7).

Excretion

After a single IV administration. the total clearance of ponesimod is3.8 L/hour. The elimination half-life after oral administration isapproximately 33 hours.

Following a single oral administration of ¹⁴C-ponesimod, 57% to 80% ofthe dose was recovered in feces (16% as unchanged ponesimod), and 10% to18% in urine (no unchanged ponesimod).

Specific Populations

Renal Impairment

No dose adjustment is necessary in patients with renal impairment. Inadult subjects with moderate or severe renal impairment (estimatedcreatinine clearance [CrCl], as determined by the Cockroft-Gault,between 30-59 mL/min for moderate and <30 mL/min for severe), there wereno significant changes in ponesimod C_(max) and AUC, compared tosubjects with normal renal function (CrCl>90 mL/min). The effect ofdialysis on the PK of ponesimod has not been studied. Due to the highplasma protein binding (greater than 99%) of ponesimod, dialysis is notexpected to alter the total and unbound ponesimod concentration, and nodose adjustments are anticipated based on these considerations.

Hepatic Impairment

In adult subjects with mild, moderate, or severe hepatic impairment(Child-Pugh class A, B and C, respectively), no change in ponesimodC_(max) was observed, but ponesimod AUC_(0-∞) was increased by 1.3-,2.0-, and 3.1-fold, respectively, compared to healthy subjects [see Usein Specific Populations (8.6)].

Age

Age (range: 17 to 65 years) was not identified to significantlyinfluence the PK of ponesimod in population pharmacokinetics analyses.The effect of age (65 years of age and older) on the pharmacokinetics ofponesimod is unknown [see Use in Specific Populations (8.5)].

Gender

Gender has no clinically significant influence on ponesimodpharmacokinetics.

Race

No clinically relevant pharmacokinetic differences were observed betweenJapanese and Caucasian subjects.

Drug Interaction Studies

Beta-Blockers

In a drug-drug interaction study. the dose titration regimen ofponesimod [see Dosage and Administration (2.2)] was administered tosubjects receiving propranolol (80 mg) once daily at steady state. Nosignificant changes in pharmacokinetics of ponesimod or propranolol wereobserved. Compared to ponesimod alone, the combination of propranololand the first dose of ponesimod (2 mg) led to a mean hourly heart ratedecrease of 12.4 bpm (90% CI: −15.6 to −9.1). Compared to ponesimodalone, propranolol administered in combination with the firstmaintenance dose of ponesimod (20 mg) led to a 7.4 bpm (90% CI: −10.9 to−3.9) mean hourly heart rate decrease.

Effect of Other Drugs on Ponesimod

In vitro studies with human liver preparations indicate that metabolismof ponesimod occurs through multiple distinct enzyme systems, includingmultiple CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12), UGT(mainly UGT1A1 and UGT2B7), and non-CYP450 oxidative enzymes, withoutmajor contribution by any single enzyme.

Ponesimod is not a substrate of P-gp, BCRP, OATP1B1, or OATP1B3transporters. Drugs that are inhibitors of these transporters areunlikely to impact the PK of ponesimod.

In vitro assessments and limited clinical data indicated thatconcomitant use of strong CYP3A4 and UGT1A1 inducers (e.g., rifampin,phenytoin, carbamazepine) may decrease the systemic exposure ofponesimod [see Drug Interactions (7.5)].

Effect of Ponesimod on Other Drugs

In vitro investigations indicate that at the recommended dose of 20 mgonce-daily, ponesimod and its metabolite M13 do not show any clinicallyrelevant drug-drug interaction potential for CYP or UGT enzymes, ortransporters.

Oral Contraceptives

Coadministration of ponesimod with an oral hormonal contraceptive(containing 1 mg norethisterone/norethindrone and 35 μg ethinylestradiol) showed no clinically relevant pharmacokinetic interactionwith ponesimod. Therefore, concomitant use of ponesimod is not expectedto decrease the efficacy of hormonal contraceptives. No interactionstudies have been performed with oral contraceptives containing otherprogestogens: however, an effect of ponesimod on their exposure is notexpected.

12. Nonclinical Toxicology

12.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Oral administration of ponesimod to mice (0, 50, 150, or 400 mg/kg/dayin males and 30, 100, or 300 mg/kg/day in females) for up to 2 yearsresulted in incidences in hemangiosarcoma and combined hemangioma andhemangiosarcoma in males at all doses and at the highest dose tested infemales. Plasma exposure (AUC) at to lowest dose tested in males (50mg/kg/day) was approximately 5 times that in humans at the recommendedhuman dose (RHD) of 20 mg.

Oral administration of ponesimod to rats (0, 3, 10, or 30 mg/kg/day inmales and 0, 10, 30 or 100 mg/kg/day in females) for up to 2 years didnot result in an increase in tumors. Plasma exposure at the highest dosetested in males (30 mg/kg/day) was approximately 4 times that in humansat the recommended human dose (RHD) of 20 mg.

Mutagenesis

Ponesimod was negative in a battery of in vitro (Ames, chromosomalaberration in mammalian cells) and in vivo (micronucleus in rat) assays.

Fertility

In separate studies. oral administration of ponesimod (0, 10, 30, or 100mg/kg/day) to male and female rats prior to and throughout the matingperiod and continuing in females to Day 6 of gestation resulted in noeffects on fertility. Plasma ponesimod exposures (AUC) at the highestdose tested were approximately 10 (males) and 30 (females) times that inhumans at the recommended human dose (RHD) of 20 mg/day.

12.2 Animal Toxicology and/or Pharmacology

Increases in lung weight and histopathology (alveolar histiocytosis,edema) were observed in oral toxicity studies in mice, rats, and dogs.At the higher doses tested in short-term studies, alveolar histiocytosiswas associated with lung edema, emphysema, or hyalinosis, and withbronchioloalveolar hyperplasia after cessation of dosing in rats andalveolar histiocytosis and hyalinosis in dogs. Effects tended to beabsent or less severe after chronic treatment. These findings areconsidered secondary to increased vascular permeability caused by SiPireceptor modulation. The NOAELs for lung findings in the 4-week oraltoxicity studies in rats and dogs were associated with plasma exposures(AUC) similar or lower than that expected in humans at the recommendedhuman dose (RHD) of 20 mg/day.

In dogs, coronary arterial lesions (thickening of the vessel wall.hyperplasia/hypertrophy of smooth muscles cells of the tunica media.subendocardial fibrosis) involving the papillary muscle of the leftventricle were observed in oral toxicity studies of 13 to 52 weeks induration. At the NOAEL (2 mg/kg/day) for these findings, plasmaexposures (AUC) were approximately 2 times that expected in humans atthe RHD.

13. Clinical Studies

The efficacy of PONVORY was demonstrated in Study 1, a randomized,double-blind, parallel group, active-controlled superiority study inpatients with relapsing forms of MS (NCT02425644). Patients were treatedfor 108 weeks. This study included patients who had an ExpandedDisability Status Scale (EDSS) score of 0 to 5.5 at baseline, hadexperienced at least one relapse within the year prior, or two relapseswithin the prior 2 years, or who had at least one gadolinium-enhancing(Gd-enhancing) lesion on a brain MRI within the prior 6 months or atbaseline. Patients with primary progressive MS were excluded.

Patients were randomized to receive either once daily PONVORY, beginningwith a 14-day dose titration [see Dosage and Administration (2.2)] orteriflunomide 14 mg. Neurological evaluations were performed atbaseline, every 3 months during the study, and at the time of asuspected relapse. Brain MRI scans were performed at baseline and atWeeks 60 and 108.

The primary endpoint was the annualized relapse rate (ARR) over thestudy period. Additional outcome measures included: 1) the number of newGd-enhancing T1 lesions from baseline to Week 108, 2) the number of newor enlarging T2 lesions (without double-counting of lesions) frombaseline to Week 108, and 3) the time to 3-month and 6-month confirmeddisability progression. A confirmed disability progression was definedas an increase of at least 1.5 in EDSS for patients with a baseline EDSSscore of 0, an increase of at least 1.0 in EDSS for patients with abaseline EDSS score of 1.0 to 5.0, or an increase of at least 0.5 inEDSS for patients with a baseline EDSS score at least 5.5, which wasconfirmed after 3 months and 6 months.

A total of 1133 patients were randomized to either PONVORY (N=567) orteriflunomide 14 mg (N=566); 86.4% of PONVORY-treated patients and 87.5%of teriflunomide 14 mg-treated patients completed the study as perprotocol. At baseline, the mean age of patients was 37 years, 97% wereWhite, and 65% were female. The mean disease duration was 7.6 years, themean number of relapses in the previous year was 1.3, and the mean EDSSscore was 2.6; 57% of patients had not received any prior non-steroidtreatments for MS. At baseline, 42.6% of patients had one or moreGd-enhancing T1 lesions (mean 2.0) on their baseline MRI scan.

The ARR was statistically significantly lower in patients treated withPONVORY than in patients who received teriflunomide 14 mg. The number ofGd-enhancing T1 lesions and the number of new or enlarging T2 lesionswere statistically significantly lower in patients treated with PONVORYthan in patients who received teriflunomide 14 mg.

There was no statistically significant difference in the 3-month and6-month confirmed disability progression outcomes between PONVORY- andteriflunomide 14 mg-treated patients over 108 weeks.

The efficacy results for Study 1 are presented in Table 22.

TABLE 22 Clinical and NMI Endpoints from Study 1 PONVORY Teriflunomide20 mg 14 mg Endpoints N = 567 N = 566 Clinical Endpoints AnnualizedRelapse Rate ^(a) 0.202 0.290 Relative reduction  30.5% (p = 0.0003)Percentage of patients without relapse ^(b) 70.7% 60.6% Proportion ofPatients with 3-month 10.8% 13.2% Confirmed Disability Progression ^(c)Hazard Ratio ^(d)   0.83 (p = 0.29) MRI Endpoints ^(b, f) Mean number ofnew or enlarging T2 1.40 3.16 hyperintense lesions per year Relativereduction 55.7% (p < 0001) Mean number of T1 Gd-enhancing 0.18 0.43lesions per MRI Relative reduction 58.5% (p < 0001) All analyses arebased on the full analysis set (FAS), which includes all randomizedpatients. N refers to the number of patients included in the FAS, pertreatment group. ^(a) Defined as confirmed relapses per year through thestudy period (Negative binomial regression model with stratificationvariables (EDSS ≤ 3.5 versus EDSS > 3.5; not-steroid treatment for MSwithin last 2 years prior to randomization [Yes/No]) and the number ofrelapses in the year prior to study entry (<=1, >=2) as marines) ^(b)Over the study period of approximately 108 weeks ^(c) Disabilityprogression defined as 1.5-point in EDSS for patients with a baselineEDSS score of 0. 1.0-point increase in EDSS for patients with a baselineEDSS score of 1.0 to 5.0. or 0.5-point increase in EDSS for patientswith a baseline EDSS score at least 5.5 confirmed 3 months later.Proportion of patients with 3-month confirmed disability progressionrefers to Kaplan-Meter estimates at Week 108. ^(d) Defined as time to 3months confirmed disability progression through the study period(Stratified Cox proportional hazard model, p-value based on thestratified log rank test) ^(e) Not statistically significant ^(f)Cumulative number of combined unique active lesions (CUALs), defined asnew or enlarging T2 lesions or Gd-enhancing T1 lesions (without doublecounting), mean lesions per year were 1.41 on ponesimod 20 mg (N = 539).and 3.16 on teriflunomide 14 mg (N = 536), a relative reduction of 56%(p < 0.0001).

A similar effect of PONVORY on the ARR and secondary MRI outcomescompared to teriflunomide 14 mg was observed in exploratory subgroupsdefined by age, gender, prior non-steroid therapy for MS, and baselinedisease activity.

14. How Supplied/Storage and Handling

14.1 How Supplied

PONVORY™ (ponesimod) tablet is available as round, biconvex, film-coatedtablets supplied in the following dosage strengths and packageconfigurations, Tables 23 and 24.

TABLE 23 Starter Pack Tablet Tablet Tablet Pack NDC Strength Color SizeTablet Debossing Size Code 2 mg White 5.0 mm “2” on one side and an archon the other side. Child NDC 3 mg Red 5.0 mm “3” on one side and an archon the other side. Resistant 50458- 4 mg Purple 5.0 mm “4” on one sideand an arch on the other side. Starter 707-14 5 mg Green 8.6 mm “5” onone side and an arch and an “A” on Pack the other side. (14 6 mg White8.6 mm “6” on one side and an arch and an “A” on tablets) the otherside. 7 mg Red 8.6 mm “7” on one side and an arch and an “A” on theother side. 8 mg Purple 8.6 mm “8” on one side and an arch and an “A” onthe other side. 9 mg Brown 8.6 mm “9” on one side and an arch and an “A”on the other side. 10 mg  Orange 8.6 mm “10” on one side and an arch andan “A” on the other side.

TABLE 24 Maintenance Dose Bottle Tablet Tablet Tablet NDC Strength ColorSize Tablet Debossing Pack Size Code 20 mg Yellow 8.6 mm “20” on oneside and an Bottle of 30 tablets with NDC arch and an “A” on thechild-resistant closure. 50458- other side. Each bottle contains a720-30 desiccant sachet and a polyester coil

14.2 Storage and Handling

Starter Pack

Store at 20° C. to 25° C. (68° F. to 77° F.); excursions permitted from15° C. to 30° C. (59° F. to 86° F.) [see USP Controlled RoomTemperature].

Store in the original package.

Maintenance Dose Bottle

Store at 20° C. to 25° C. (68° F. to 77° F.); excursions permitted from15° C. to 30° C. (59° F. to 86° F.) [see USP Controlled RoomTemperature].

Store in the original package. Do not discard desiccant. Protect frommoisture. Keep out of reach of children.

15. Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (MedicationGuide).

Administration

Tell patients not to discontinue PONVORY without first discussing thiswith the prescribing healthcare provider. Advise patients to contacttheir healthcare provider if they accidently take more PONVORY thanprescribed.

Instruct patients to administer tablets whole.

Risk of Infections

Inform patients that they may have an increased risk of infections, someof which could be life-threatening, when taking PONVORY and for 1 to 2weeks after stopping it, and that they should contact their healthcareprovider if they develop symptoms of infection [see Warnings andPrecautions (5.1)]. Advise patients that the use of some vaccinescontaining live virus (live attenuated vaccines) should be avoidedduring treatment with PONVORY, and PONVORY should be paused 1 week priorand until 4 weeks after a planned vaccination. Recommend that patientspostpone treatment with PONVORY for at least 1 month after VZVvaccination. Inform patients that prior or concomitant use of drugs thatsuppress the immune system may increase the risk of infection.

Cardiac Effects

Advise patients that initiation of PONVORY treatment results intransient decrease in heart rate [see Warnings and Precautions (5.2)].Inform patients that to reduce this effect, dose titration is required.Advise patients that dose titration is also required if 4 or moreconsecutive daily doses are missed during treatment initiation ormaintenance treatment [see Dosage and Administration (2.2, 2.4) andWarnings and Precautions (5.2)]. Inform certain patients with certainpreexisting cardiac conditions that they will need to be observed in thedoctor's office or other facility for at least 4 hours after the firstdose and after re-initiation if treatment is interrupted or discontinuedfor certain periods [see Dosage and Administration (2.3)].

Respiratory Effects

Advise patients that they should contact their healthcare provider ifthey experience new onset or worsening of dyspnea [see Warnings andPrecautions (5.3)].

Liver Injury

Inform patients that PONVORY may increase liver enzymes. Advise patientthat they should contact their healthcare provider if they experienceany unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, orjaundice and/or dark urine during treatment [see Warnings andPrecautions (5.4)].

Cutaneous Malignancies

Inform patients that the risk of basal cell carcinoma is increased withthe use of PONVORY and that cases of melanoma and squamous cellcarcinoma have been reported. Advise patients that any suspicious skinlesions should be promptly evaluated. Advise patients to limit exposureto sunlight and ultraviolet light by wearing protective clothing andusing a sunscreen with high protection factor [see Warnings andPrecautions (5.6)].

Pregnancy and Fetal Risk

Inform patients that, based on animal studies, PONVORY may cause fetalharm. Discuss with women of childbearing age whether they are pregnant,might be pregnant, or are trying to become pregnant. Advise women ofchildbearing potential of the need for effective contraception duringtreatment with PONVORY and for one week after stopping PONVORY. Advise afemale patient to immediately inform her healthcare provider if she ispregnant or planning to become pregnant [see Warnings and Precautions(5.7)].

Macular Edema

Advise patients that PONVORY may cause macular edema, and that theyshould contact their healthcare provider if they experience any changesin their vision while taking PONVORY [see Warnings and Precautions(5.8)]. Inform patients with diabetes mellitus or a history of uveitisthat their risk of macular edema is increased.

Posterior Reversible Encephalopathy Syndrome

Advise patients to immediately report to their healthcare provider anysymptoms involving sudden onset of severe headache, altered mentalstatus, visual disturbances, or seizure. Inform patients that delayedtreatment could lead to permanent neurological sequelae [see Warningsand Precautions (5.9)].

Severe Increase in Disability After Stopping PONVORY

Inform patients that severe increase in disability has been reportedafter discontinuation of another S1P receptor modulator like PONVORY.Advise patients to contact their healthcare provider if they developworsening symptoms of MS following discontinuation of PONVORY [seeWarnings and Precautions (5.11)].

Immune System Effects After Stopping PONVORY

Advise patients that PONVORY continues to have effects, such as loweringeffects on peripheral lymphocyte count, for 1 to 2 weeks after the lastdose [see Warnings and Precautions (5.12)].

Active ingredient made in Austria.

Manufactured for: Janssen Pharmaceuticals. Inc. Titusville. N.J. 08560 ©2021 Janssen Pharmaceutical Companies

Medication Guide

PONVORY™ (pon-VOR-ee) (ponesimod) tablets, for oral use

What is the most important information I should know about PONVORY?

PONVORY may cause serious side effects. including:

Infections. PONVORY can increase your risk of serious infections thatcan be life-threatening and cause death. PONVORY lowers the number ofwhite blood cells (lymphocytes) in your blood. This will usually go backto normal within 1 to 2 weeks of stopping treatment. Your healthcareprovider should review a recent blood test of your white blood cellsbefore you start taking PONVORY.

Call your healthcare provider right away if you have any of thesesymptoms of an infection during treatment with PONVORY and for 1 to 2weeks after your last dose of PONVORY:

fever

tiredness

body aches

chills

nausea

vomiting

headache with fever, neck stiffness, sensitivity to light, nausea, orconfusion (these may be symptoms of meningitis, an infection of thelining around your brain and spine).

Your healthcare provider may delay starting or may stop your PONVORYtreatment if you have an infection.

Slow heart rate (bradycardia or bradyarrhythmia) when you start takingPONVORY. PONVORY can cause your heart rate to slow down, especiallyafter you take your first dose. You should have a test to check theelectrical activity of your heart called an electrocardiogram (ECG)before you take your first dose of PONVORY.

Only start your treatment with PONVORY using the Starter Pack. You mustuse the PONVORY Starter Pack to slowly increase the dose over a 14-dayperiod to help reduce the effect of slowing of your heart rate. It isimportant to follow the recommended dosing instructions. See “How shouldI take PONVORY?”

Call your healthcare provider if you experience the following symptomsof slow heart rate:

dizziness

lightheadedness

feeling like your heart is beating slowly or skipping beats

shortness of breath

confusion

chest pain

tiredness.

Follow directions from your healthcare provider when starting PONVORYand when you miss a dose. See “How should I take PONVORY?”

See “What are possible side effects of PONVORY?” for more informationabout side effects.

What is PONVORY?

PONVORY is a prescription medicine that is used to treat relapsing formsof multiple sclerosis, to include clinically isolated syndrome,relapsing-remitting disease, and active secondary progressive disease,in adults.

It is not known if PONVORY is safe and effective in children.

Do not take PONVORY if you:

have had a heart attack, chest pain called unstable angina, stroke ormini-stroke (transient ischemic attack or TIA), or certain types ofheart failure in the last 6 months.

have certain types of heart block or irregular or abnormal heartbeat(arrhythmia), unless you have a pacemaker.

Talk to your healthcare provider before taking PONVORY if you have anyof these conditions, or do not know if you have any of these conditions.

Before you take PONVORY, tell your healthcare provider about all of yourmedical conditions, including if you:

have a fever or infection, or you are unable to fight infections due toa disease or taking medicines that weaken your immune system.

have had chicken pox or have received the vaccine for chicken pox. Yourhealthcare provider may do a blood test for chicken pox virus. You mayneed to get the full course of vaccine for chicken pox and then wait 1month before you start taking PONVORY.

have slow heart rate.

have an irregular or abnormal heartbeat (arrhythmia).

have a history of stroke.

have heart problems, including a heart attack or chest pain.

have breathing problems, including during your sleep (sleep apnea).

have liver problems.

have high blood pressure.

had or now have a type of skin cancer called basal cell carcinoma (BCC),melanoma, or squamous cell carcinoma.

have eye problems, especially an inflammation of the eye called uveitis.have diabetes.

are pregnant or plan to become pregnant. PONVORY may harm your unbornbaby. Talk with your healthcare provider if you are pregnant or plan tobecome pregnant. If you are a woman who can become pregnant, you shoulduse effective birth control during your treatment with PONVORY and for 1week after you stop taking PONVORY. Talk to your healthcare providerabout what method of birth control is right for you during this time.Tell your healthcare provider right away if you do become pregnant whiletaking PONVORY or within 1 week after you stop taking PONVORY.

are breastfeeding or plan to breastfeed. It is not known if PONVORYpasses into your breast milk. Talk to your healthcare provider about thebest way to feed your baby if you take PONVORY.

Tell your healthcare provider about all the medicines you take,including prescription medicines, over-the-counter medicines, vitamins,and herbal supplements.

Using PONVORY and other medicines together may affect each other causingserious side effects.

Especially tell your healthcare provider if you take or have taken:

medicines to control your heart rhythm (antiarrhythmics), or bloodpressure (antihypertensives), or heart beat (such as calcium channelblockers or beta-blockers).

medicines that affect your immune system, such as alemtuzumab.

medicines such as rifampin, phenytoin, or carbamazepine.

You should not receive live vaccines during treatment with PONVORY, forat least 1 month before taking PONVORY, and for 1 to 2 weeks after youstop taking PONVORY. If you receive a live vaccine, you may get theinfection the vaccine was meant to prevent. Vaccines may not work aswell when given during treatment with PONVORY.

Talk with your healthcare provider if you are not sure if you take anyof these medicines.

Know the medicines you take. Keep a list of your medicines with you toshow your healthcare provider and pharmacist when you get a newmedicine.

How should I take PONVORY?

You will receive a 14-day starter pack. You must start PONVORY by slowlyincreasing doses over the first two weeks. Follow the dose schedule inTable 25 below. This may reduce the risk of slowing of the heart rate.

TABLE 25 Dose Schedule Daily Dose Starter Pack Day Day 1 2 mg tablet 1time a day Day 2 2 mg tablet 1 time a day Day 3 3 mg tablet 1 time a dayDay 4 3 mg tablet 1 time a day Day 5 4 mg tablet 1 time a day Day 6 4 mgtablet 1 time a day Day 7 5 mg tablet 1 time a day Day 8 6 mg tablet 1time a day Day 9 7 mg tablet 1 time a day Day 10 8 mg tablet 1 time aday Day 11 9 mg tablet 1 time a day Day 12 10 mg tablet 1 time a day Day13 10 mg tablet 1 time a day Day 14 10 mg tablet 1 time a dayMaintenance Day 15 and thereafter 20 mg tablet 1 time a day

Take PONVORY exactly as your healthcare provider tells you to take it.

Take PONVORY 1 time each day.

Swallow PONVORY tablets whole.

Take PONVORY with or without food.

Do not stop taking PONVORY without talking to your healthcare providerfirst.

Do not skip a dose.

Start taking PONVORY with a 14-day starter pack.

If you miss taking 1, 2, or 3 tablets in a row of PONVORY in the 14-daystarter pack, continue treatment by taking the first dose you missed.Take 1 tablet as soon as you remember. Then, take 1 tablet a day tocontinue with the starter pack dose as planned.

If you miss taking 1, 2, or 3 tablets in a row of PONVORY while takingthe 20 mg maintenance dose, continue treatment with the 20 mgmaintenance dose.

If you miss taking 4 or more tablets in a row of PONVORY, while takingthe 14-day starter pack or the 20 mg maintenance dose, you need torestart treatment with a new 14-day starter pack. Call your healthcareprovider if you miss 4 or more doses of PONVORY. Do not restart PONVORYafter stopping it for 4 or more days in a row without talking to yourhealthcare provider. If you have certain heart conditions, you may needto be monitored by your healthcare provider for at least 4 hours whenyou take your next dose.

Write down the date you start taking PONVORY so you will know if youmiss 4 or more doses in a row.

What are the possible side effects of PONVORY?

PONVORY may cause serious side effects, including:

See “What is the most important information I should know aboutPONVORY?”

breathing problems. Some people who take PONVORY have shortness ofbreath. Call your healthcare provider right away if you have new orworsening breathing problems.

liver problems. PONVORY may cause liver problems. Your healthcareprovider should do blood tests to check your liver before you starttaking PONVORY. Call your healthcare provider right away if you have anyof the following symptoms of liver problems:

unexplained nausea

vomiting

stomach (abdominal) pain

tiredness

loss of appetite

yellowing of the whites of your eyes or skin

dark urine.

increased blood pressure. Your healthcare provider should check yourblood pressure during treatment with PONVORY.

types of skin cancer called basal cell carcinoma (BCC), melanoma, andsquamous cell carcinoma. Certain types of skin cancer have happened withdrugs in the same class. Tell your healthcare provider if you have anychanges in the appearance of your skin, including changes in a mole, anew darkened area on your skin, a sore that does not heal, or growths onyour skin, such as a bump that may be shiny. pearly white, skin-colored,or pink. Your doctor should check your skin for any changes duringtreatment with PONVORY. Limit the amount of time you spend in sunlightand ultraviolet (UV) light. Wear protective clothing and use a sunscreenwith a high sun protection factor.

a problem with your vision called macular edema. Tell your healthcareprovider about any changes in your vision. Your healthcare providershould test your vision before you start taking PONVORY and any time younotice vision changes during treatment with PONVORY. Your risk ofmacular edema is higher if you have diabetes or have had an inflammationof your eye called uveitis.

Call your healthcare provider right away if you have any of thefollowing symptoms:

blurriness or shadows in the center of your vision

a blind spot in the center of your vision

sensitivity to light

unusually colored (tinted) vision.

swelling and narrowing of the blood vessels in your brain. A conditioncalled Posterior Reversible Encephalopathy Syndrome (PRES) has happenedwith drugs in the same class. Symptoms of PRES usually get better whenyou stop taking PONVORY. However, if left untreated, it may lead to astroke. Call your healthcare provider right away if you have any of thefollowing symptoms:

sudden severe headache

sudden confusion

sudden loss of vision or other changes in your vision

seizure.

severe worsening of multiple sclerosis (MS) after stopping PONVORY. WhenPONVORY is stopped, symptoms of MS may return and become worse comparedto before or during treatment. Always talk to your healthcare providerbefore you stop taking PONVORY for any reason. Tell your healthcareprovider if you have worsening symptoms of MS after stopping PONVORY.

The most common side effects of PONVORY include:

upper respiratory tract infections

elevated liver enzymes (abnormal liver tests)

high blood pressure.

These are not all of the possible side effects of PONVORY.

For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. Youmay report side effects to FDA at 1-800-FDA-1088.

How should I store PONVORY?

Store PONVORY at room temperature between 68° F. to 77° F. (20° C. to25° C.).

Store PONVORY in the original package.

The bottle of PONVORY contains a desiccant sachet to help keep yourmedicine dry (protect it from moisture Do not throw away (discard) thedesiccant.

Keep PONVORY and all medicines out of the reach of children.

General information about the safe and effective use of PONVORY.

Medicines are sometimes prescribed for purposes other than those listedin a Medication Guide. Do not use PONVORY for conditions for which itwas not prescribed. Do not give PONVORY to other people, even if theyhave the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information aboutPONVORY that is written for health professionals.

What are the ingredients in PONVORY?

Active ingredient: ponesimod

Inactive ingredients:

Tablet core: croscarmellose sodium, lactose monohydrate, magnesiumstearate, microcrystalline cellulose, povidone K30, silica colloidalanhydrous, and sodium lauryl sulfate.

Tablet coating: ferrosoferric oxide (included in 4 mg, 5 mg, 8 mg, and 9mg film-coated tablets), Hydroxypropyl methylcellulose 2910, iron oxidered (included in 3 mg, 4 mg, 7 mg, 8 mg, 9 mg, and 10 mg film-coatedtablets), iron oxide yellow (included in 3 mg, 5 mg, 7 mg, 9 mg, 10 mgand 20 mg film-coated tablets), lactose monohydrate, polyethylene glycol3350, titanium dioxide, and triatetin.

Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, N.J. 08560

© 2021 Janssen Pharmaceutical Companies

For more information, go to www.ponvory.com or call 1-800-526-7736.

This Medication Guide has been approved by the U.S. Food and DrugAdministration Approved: March/2021

What is claimed:
 1. A method for reducing clinical management eventsbefore or during treatment of multiple sclerosis in a patient in needthereof, comprising administering ponesimod in an amount and manner thatis described in a drug product label for an approved drug product. 2.The method of claim 1, wherein about 20 mg of ponesimod is administeredorally once daily.
 3. The method of claim 1, wherein the treatmentcomprises an up-titration step at initiation of the method or uponre-initiation of the method after a discontinuation, comprisingadministering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mgof ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg ofponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day9; 8 mg of ponesimod on day 10; and 9 mg of ponesimod on day 11; 10 mgof ponesimod on days 12, 13, and 14, followed by administering 20 mg ofponesimod once daily thereafter.
 4. The method of claim 1, wherein themultiple sclerosis is relapsing multiple sclerosis.
 5. The method ofclaim 4, wherein the relapsing multiple sclerosis comprisesrelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.
 6. The method of claim 1, wherein theclinical management event comprises first-dose monitoring, genotyping,an eye exam, drug-drug interactions (DDI), or a liver function test, orcombinations thereof.
 7. The method of claim 6, wherein the reduction isrelative to a patient population at substantially the same level ofdisease progression receiving a standard of care treatment comprising anSI P receptor modulator other than ponesimod.
 8. The method of claim 7,wherein the standard of care treatment comprises fingolimod, siponimod,or ozanimod.
 9. A pharmaceutical product comprising ponesimod, whereinthe pharmaceutical product is packaged, and wherein the package includesa label that identifies ponesimod as an approved drug product for thetreatment of multiple sclerosis.
 10. An approved drug product as definedherein, wherein the pharmaceutical product comprises ponesimod in tabletform.
 11. The approved drug product of claim 10, wherein thepharmaceutical product comprises the 14-day dose titration prior to themaintenance dosage of 20 mg.
 12. The approved drug product of claim 11,wherein the pharmaceutical product demonstrated a statisticallysignificant lower number of Gd-enhancing T1 lesions and/or astatistically significant lower number of new or enlarging T2 lesionscompared to the patients in the patient population that wereadministered a once daily 14 mg dosage of teriflunomide.
 13. Theapproved drug product of claim 11, wherein the patients in the patientpopulation were treated for 108 weeks and annualized relapse rate wasreduced by 30.5% compared to the patients in the patient population thatwere administered a once daily 14 mg dosage of teriflunomide.
 14. Amethod for concomitant treatment of a beta-blocker and ponesimod in apatient in need thereof, wherein the patient is being treated with thebeta-blocker and ponesimod treatment is to be initiated, and wherein thepatient has a resting heart rate of greater than 55 beats per minuteduring treatment with the beta-block and prior to initiation ofponesimod, comprising administering ponesimod without interruption tothe beta-blocker treatment.
 15. The method of claim 14, wherein 20 mg ofthe ponesimod is administered orally once daily.
 16. The method of claim14, wherein the ponesimod administration comprises an up-titrationcomprising administering orally once daily 2 mg of ponesimod on days 1and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg ofponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod onday 11; and 10 mg of ponesimod on days 12, 13, and 14, followed byadministering 20 mg of ponesimod once daily thereafter.
 17. The methodof claim 14, wherein the beta-blocker comprises propranol.
 18. Themethod of claim 17, wherein 80 mg of the propranol is administeredorally once daily.
 19. The method of claim 14, wherein the patient is inneed of treatment for relapsing forms of multiple sclerosis.
 20. Themethod of claim 19, wherein the relapsing forms of multiple sclerosiscomprise relapsing-remitting disease, clinically isolated syndrome, oractive secondary progressive disease.
 21. A method for concomitanttreatment of a beta-blocker and ponesimod for a patient in need thereof,wherein the patient is being treated with the beta-blocker and ponesimodtreatment is to be initiated, and wherein the patient has a restingheart rate of less than or equal to 55 beats per minute during treatmentwith the beta-block and prior to initiation of ponesimod, comprisinginterrupting the beta-blocker treatment until the patient's heart rateis greater than 55 beats per minute and initiating ponesimod treatmentin a titration regimen comprising administering orally once daily 2 mgof ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg ofponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimodon day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mgof ponesimod on day 11; and 10 mg of ponesimod on days 12, 13, and 14,followed by administering a 20 mg maintenance dose of ponesimod oncedaily thereafter, and reinitiating the beta-blocker after ponesimod hasbeen up-titrated to the maintenance dosage.
 22. The method of claim 21,wherein the beta-blocker comprises propranol.
 23. The method of claim22, wherein 80 mg of the propranol is administered orally once daily.24. The method of claim 21, wherein the patient is in need of treatmentfor relapsing forms of multiple sclerosis.
 25. The method of claim 24,wherein the relapsing forms of multiple sclerosis compriserelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.
 26. A method of treating multiplesclerosis in a patient in need thereof, wherein the patient has sinusbradycardia, first or second degree AV block, or a history of myocardialinfarction or heart failure occurring more than 6 months prior to theinitiation of ponesimod treatment, comprising administering an effectiveregimen of ponesimod to the patient, wherein after a first dose of theponesimod, the patient is monitored for a period of 4 hours for symptomsof bradycardia.
 27. The method of claim 26, wherein no first dosemonitoring is needed wherein the patient has no sinus bradycardia, nofirst or second degree AV block, and no history of myocardial infarctionor heart failure occurring more than 6 months prior to the initiation ofponesimod treatment.
 28. The method of claim 26, wherein the monitoringcomprises pulse and blood pressure measurements.
 29. The method of claim26, wherein an electrocardiogram (ECG) of the patient is obtained at theend of the four hour monitoring period and before continued dosing. 30.The method of claim 26, wherein the monitoring is repeated for anotherfour hour period after a second dose.
 31. A method of reinitiatingtreatment with ponesimod following a missed dose in a patient in needthereof, wherein the patient is being treated with an oral, once daily20 mg maintenance dose and fewer than four consecutive maintenance doseshave been missed, comprising resuming treatment with the maintenancedose.
 32. The method of claim 31, wherein the patient is in need oftreatment for relapsing forms of multiple sclerosis.
 33. The method ofclaim 32, wherein the relapsing forms of multiple sclerosis compriserelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.
 34. A method of reinitiating treatmentwith ponesimod following a missed dose for a patient in need thereof,wherein the patient is being treated with titration doses comprisingadministering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mgof ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg ofponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mgof ponesimod on days 12, 13, and 14, followed by administering 20 mg ofponesimod once daily, and fewer than four consecutive titration doseshave been missed, comprising resuming treatment with the first missedtitration dose and resuming the titration at that dose and titrationday.
 35. The method of claim 34, wherein the patient is in need oftreatment for relapsing forms of multiple sclerosis.
 36. The method ofclaim 35, wherein the relapsing forms of multiple sclerosis compriserelapsing-remitting disease, clinically isolated syndrome, or activesecondary progressive disease.
 37. A method of reinitiating ponesimodfollowing a missed dose for a patient in need thereof, wherein thepatient is being treated with an oral, once daily 20 mg maintenance doseor a 14-day titration regimen comprising administering orally once dailytitration doses of 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimodon days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod onday 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg ofponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimodon days 12, 13, and 14, and four or more consecutive maintenance dosesor titration doses have been missed, comprising reinitiating ponesimodwith the 14-day titration regimen.
 38. The method of claim 37, whereinthe patient is in need of treatment for relapsing forms of multiplesclerosis.
 39. The method of claim 38, wherein the relapsing forms ofmultiple sclerosis comprise relapsing-remitting disease, clinicallyisolated syndrome, or active secondary progressive disease.